ANAEROBIC AND AEROBIC OXIDATION
OF GLUCOSE. ALTERNATIVE WAYS OF MONOSACCHARIDE METABOLISM. STUDING OF
BIOSYNTHESIS AND CATABOLISM OF GLYCOGEN. REGULATION OF GLYCOGEN METABOLISM.
BIOSYNTHESIS OF GLUCOSE – GLUCONEOGENESIS. METABOLISM OF LIPIDS: DIGESTION, ABSORBTION,
RESYNTHESIS IN THE INTESTINAL WALL. METABOLISM OF LIPIDS: OXIDATION AND BIOSYNTHESIS
OF FATTY
ACIDS, TRIACYLGLYCEROLS
AND PHOSPHOLIPIDS. BIOSYNTHESIS AND BIOTRANSFORMATION OF CHOLESTEROL.
METABOLISM OF KETONE
BODIES. REGULATION AND DISORDERS OF
LIPID METABOLISM. DIGESTION OF
PROTEINS. GENERAL PATHWAYS OF AMINO ACIDS TRANSFORMATION. DETOXIFICATION
OF AMMONIA AND BIOSYNTHESIS OF UREA.
Carbohydrates
Carbohydrates have the general
molecular formula CH2O, and thus were once thought to represent
"hydrated carbon". However, the arrangement of atoms in carbohydrates
has little to do with water molecules.
http://www.youtube.com/watch?v=p-lFJVOkFwk
Starch and cellulose are two
common carbohydrates. Both are macromolecules with molecular weights in the hundreds of thousands.
Both are polymers (hence "polysaccharides"); that is,
each is built from repeating units, monomers, much as a chain is built from its links.
The monomers of both starch and
cellulose are the same: units of the sugar glucose.
Sugars
Monosaccharides
Three common
sugars share the same molecular formula: C6H12O6.
Because of their six carbon atoms, each is a hexose.
They are:
·
glucose, "blood
sugar", the immediate source of energy for cellular
respiration
·
galactose, a sugar in
milk (and yogurt), and
·
fructose, a sugar
found in honey.
Although all three share the same molecular formula (C6H12O6),
the arrangement of atoms differs in each case. Substances such as these three, which
have identical molecular formulas but different structural formulas, are known
as structural isomers.
Glucose, galactose, and fructose are
"single" sugars or monosaccharides. Two monosaccharides can be
linked together to form a "double" sugar or disaccharide.
Disaccharides
Three
common disaccharides:
·
sucrose — common
table sugar = glucose + fructose
·
lactose — major
sugar in milk = glucose + galactose
·
maltose — product of
starch digestion = glucose + glucose
Although the process of linking the two monomers is
rather complex, the end result in each case is the loss of a hydrogen atom (H)
from one of the monosaccharides and a hydroxyl group (OH) from the other. The
resulting linkage between the sugars is called a glycosidic bond. The
molecular formula of each of these disaccharides is
C12H22O11 = 2 C6H12O6
− H2O
All sugars are very soluble in water because of their
many hydroxyl groups. Although not as concentrated a fuel as fats, sugars are
the most important source of energy for many cells.
Carbohydrates provide the bulk of the calories (4 kcal/gram)
in most diets, and starches provide the bulk of that. Starches are
polysaccharides.
Polysaccharides
Starches
Starches are polymers of glucose. Two
types are found:
·
amylose consists of
linear, unbranched chains of several hundred glucose residues (units). The
glucose residues are linked by a glycosidic bond between their #1 and #4 carbon
atoms.
·
amylopectin
differs from amylose in being highly branched. At approximately every thirtieth
residue along the chain, a short side chain is attached by a glycosidic bond to
the #6 carbon atom (the carbon above the ring). The total number of glucose
residues in a molecule of amylopectin is several thousand.
Starches are insoluble in water
and thus can serve as storage depots of glucose. Plants convert excess glucose
into starch for storage. The image shows starch grains (lightly stained with
iodine) in the cells of the white potato. Rice, wheat, and corn are also major
sources of starch in the human diet.
Before starches can
enter (or leave) cells, they must be
digested. The hydrolysis of starch is done by amylases. With the aid of an amylase
(such as pancreatic amylase), water molecules enter at the 1 -> 4 linkages,
breaking the chain and eventually producing a mixture of glucose and maltose.
A different amylase is needed to break the 1 -> 6 bonds of amylopectin.
http://www.youtube.com/watch?v=AEsQxzeAry8
http://www.youtube.com/watch?v=KED6BHVM97s&feature=related
Glycogen
Animals store excess glucose by
polymerizing it to form glycogen. The structure of glycogen is similar
to that of amylopectin, although the branches in glycogen tend to be shorter
and more frequent.
Glycogen is broken back down
into glucose when energy is needed (a process called glycogenolysis).
http://www.youtube.com/watch?v=D2RFc1D_Iv0&feature=related
In glycogenolysis,
·
phosphate groups — not water — break
the 1 -> 4 linkages
·
the phosphate group must then be
removed so that glucose can leave the cell.
The liver and skeletal muscle
are major depots of glycogen.
There is some evidence that
intense exercise and a high-carbohydrate diet ("carbo-loading") can
increase the reserves of glycogen in the muscles and thus may help marathoners
work their muscles somewhat longer and harder than otherwise. But for most of
us, carbo loading leads to increased deposits of fat.
Cellulose
Cellulose is probably the single
most abundant organic molecule in the biosphere. It is the major structural
material of which plants are made. Wood is largely cellulose while cotton and
paper are almost pure cellulose.
Like starch, cellulose is a
polysaccharide with glucose as its monomer. However, cellulose differs profoundly from starch in its
properties.
·
Because of the orientation of the glycosidic
bonds linking the glucose residues, the rings of glucose are arranged in a
flip-flop manner. This produces a long, straight, rigid molecule.
·
There are no side chains in cellulose
as there are in starch. The absence of side chains allows these linear
molecules to lie close together.
·
Because of the many -OH groups, as
well as the oxygen atom in the ring, there are many opportunities for hydrogen bonds
to form between adjacent chains.
The result is a series of stiff,
elongated fibrils — the perfect material for building the cell walls of plants.
This electron micrograph
(courtesy of R. D. Preston) shows the cellulose fibrils in the cell wall of a green alga. These long, rigid fibrils are a clear reflection of
the nature of the cellulose molecules of which they are composed.
Carbohydrates and Metabolism Chart - Carb Chart
Digestion of
Dietary Carbohydrates
Dietary carbohydrate from which humans gain energy
enter the body in complex forms, such as disaccharides and the polymers starch (amylose and amylopectin) and glycogen. The polymer cellulose is also consumed but not
digested. The first step in the metabolism of digestible carbohydrate is the
conversion of the higher polymers to simpler, soluble forms that can be
transported across the intestinal wall and delivered to the tissues. The
breakdown of polymeric sugars begins in the mouth. Saliva has a slightly acidic
pH of 6.8 and contains lingual amylase that begins the digestion of
carbohydrates. The action of lingual amylase is limited to the area of the
mouth and the esophagus; it is virtually inactivated by the much stronger acid
pH of the stomach. Once the food has arrived in the stomach, acid hydrolysis
contributes to its degradation; specific gastric proteases and lipases aid this
process for proteins and fats, respectively. The mixture of gastric secretions,
saliva, and food, known collectively as chyme, moves to the small
intestine.
The main polymeric-carbohydrate digesting enzyme of
the small intestine is -amylase. This enzyme is secreted by the
pancreas and has the same activity as salivary amylase, producing disaccharides
and trisaccharides. The latter are converted to monosaccharides by intestinal
saccharidases, including maltases that hydrolyze di- and trisaccharides, and
the more specific disaccharidases, sucrase, lactase, and trehalase. The net
result is the almost complete conversion of digestible carbohydrate to its
constituent monosaccharides. The resultant glucose and other simple
carbohydrates are transported across the intestinal wall to the hepatic portal
vein and then to liver parenchymal cells and other tissues. There they are
converted to fatty acids, amino acids, and glycogen, or else oxidized by the
various catabolic pathways of cells.
Oxidation of glucose is known as glycolysis.Glucose is oxidized to
either lactate or pyruvate. Under aerobic conditions, the dominant product in
most tissues is pyruvate and the
pathway is known as aerobic glycolysis.
When oxygen is depleted, as for instance during prolonged vigorous exercise, the
dominant glycolytic product in many tissues is lactate and the process is known as anaerobic glycolysis.
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The Energy
Derived from Glucose Oxidation
Aerobic glycolysis of glucose to
pyruvate, requires two equivalents of ATP to activate the process, with the
subsequent production of four equivalents of ATP and two equivalents of NADH.
Thus, conversion of one mole of glucose to two moles of pyruvate is accompanied
by the net production of two moles each of ATP and NADH.
Glucose + 2 ADP + 2 NAD+ + 2 Pi
-----> 2 Pyruvate + 2 ATP + 2 NADH + 2 H+
The NADH generated during glycolysis
is used to fuel mitochondrial ATP synthesis via oxidative phosphorylation, producing either
two or three equivalents of ATP depending upon whether the glycerol phosphate shuttle or the malate-aspartate shuttle is used to
transport the electrons from cytoplasmic NADH into the mitochondria. The net
yield from the oxidation of 1 mole of glucose to 2 moles of pyruvate is,
therefore, either 6 or 8 moles of ATP. Complete oxidation of the 2 moles of
pyruvate, through the TCA cycle, yeilds an additional 30 moles of
ATP; the total yield, therefore being either 36 or 38 moles of ATP from the
complete oxidation of 1 mole of glucose to CO2 and H2O.
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The
Individual Reactions of Glycolysis
The pathway of glycolysis can be seen
as consisting of 2 separate phases. The first is the chemical priming phase
requiring energy in the form of ATP, and the second is considered the
energy-yielding phase. In the first phase, 2 equivalents of ATP are used to
convert glucose to fructose 1,6-bisphosphate (F1,6BP). In the second phase
F1,6BP is degraded to pyruvate, with the production of 4 equivalents of ATP and
2 equivalents of NADH.
http://www.youtube.com/watch?v=6JGXayUyNVw&feature=related
http://www.youtube.com/watch?v=nKgUBsC4Oyo&feature=related
Pathway of glycolysis from glucose to
pyruvate. Substrates and products are in blue, enzymes are in green. The two
high energy intermediates whose oxidations are coupled to ATP synthesis are
shown in red (1,3-bisphosphoglycerate and phosphoenolpyruvate).
http://www.youtube.com/watch?v=PQMsJSme780&feature=related
The Hexokinase Reaction:
The ATP-dependent phosphorylation of
glucose to form glucose 6-phosphate (G6P)is the first reaction of glycolysis, and
is catalyzed by tissue-specific isoenzymes known as hexokinases. The
phosphorylation accomplishes two goals: First, the hexokinase reaction converts
nonionic glucose into an anion that is trapped in the cell, since cells lack
transport systems for phosphorylated sugars. Second, the otherwise biologically
inert glucose becomes activated into a labile form capable of being further
metabolized.
Four mammalian isozymes of hexokinase
are known (Types I - IV), with the Type IV isozyme often referred to as glucokinase.
Glucokinase is the form of the enzyme found in hepatocytes. The high Km
of glucokinase for glucose means that this enzyme is saturated only at very
high concentrations of substrate.
Comparison of the activities of
hexokinase and glucokinase. The Km for hexokinase is significantly
lower (0.1mM) than that of glucokinase (10mM). This difference ensures that
non-hepatic tissues (which contain hexokinase) rapidly and efficiently trap
blood glucose within their cells by converting it to glucose-6-phosphate. One
major function of the liver is to deliver glucose to the blood and this in
ensured by having a glucose phosphorylating enzyme (glucokinase) whose Km
for glucose is sufficiently higher that the normal circulating concentration of
glucose (5mM).
This feature of hepatic glucokinase
allows the liver to buffer blood
glucose. After meals, when postprandial blood glucose levels are high, liver
glucokinase is significantly active, which causes the liver preferentially to
trap and to store circulating glucose. When blood glucose falls to very low
levels, tissues such as liver and kidney, which contain glucokinases but are
not highly dependent on glucose, do not continue to use the meager glucose
supplies that remain available. At the same time, tissues such as the brain,
which are critically dependent on glucose, continue to scavenge blood glucose
using their low Km hexokinases, and as a consequence their viability
is protected. Under various conditions of glucose deficiency, such as long
periods between meals, the liver is stimulated to supply the blood with glucose
through the pathway of gluconeogenesis. The levels of glucose
produced during gluconeogenesis are insufficient to activate glucokinase,
allowing the glucose to pass out of hepatocytes and into the blood.
The regulation of hexokinase and
glucokinase activities is also different. Hexokinases I, II, and III are
allosterically inhibited by product (G6P) accumulation, whereas glucokinases
are not. The latter further insures liver accumulation of glucose stores during
times of glucose excess, while favoring peripheral glucose utilization when
glucose is required to supply energy to peripheral tissues.
Phosphohexose Isomerase:
The second reaction of glycolysis is an isomerization,
in which G6P is converted to fructose 6-phosphate (F6P). The enzyme catalyzing
this reaction is phosphohexose isomerase (also known as phosphoglucose
isomerase). The reaction is freely reversible at normal cellular concentrations
of the two hexose phosphates and thus catalyzes this interconversion during
glycolytic carbon flow and during gluconeogenesis.
6-Phosphofructo-1-Kinase (Phosphofructokinase-1,
PFK-1):
The next reaction of glycolysis involves the
utilization of a second ATP to convert F6P to fructose 1,6-bisphosphate
(F1,6BP). This reaction is catalyzed by 6-phosphofructo-1-kinase, better known
as phosphofructokinase-1 or PFK-1. This reaction is not readily
reversible because of its large positive free energy (G0'
= +5.4 kcal/mol) in the reverse direction. Nevertheless, fructose units readily
flow in the reverse (gluconeogenic) direction because of the ubiquitous
presence of the hydrolytic enzyme, fructose-1,6-bisphosphatase (F-1,6-BPase).
The presence of these two enzymes in the same cell
compartment provides an example of a metabolic futile cycle, which if
unregulated would rapidly deplete cell energy stores. However, the activity of
these two enzymes is so highly regulated that PFK-1 is considered to be the rate-limiting enzyme of glycolysis and
F-1,6-BPase is considered to be the rate-limiting
enzyme in gluconeogenesis.
Aldolase:
Aldolase catalyses the hydrolysis of F1,6BP into two 3-carbon
products: dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate
(G3P). The aldolase reaction proceeds readily in the reverse direction, being
utilized for both glycolysis and gluconeogenesis.
Triose Phosphate Isomerase: \
The two products of the aldolase reaction equilibrate
readily in a reaction catalyzed by triose phosphate isomerase. Succeeding
reactions of glycolysis utilize G3P as a substrate; thus, the aldolase reaction
is pulled in the glycolytic direction by mass action principals.
Glyceraldehyde-3-Phosphate Dehydrogenase:
The second phase of glucose catabolism features the
energy-yielding glycolytic reactions that produce ATP and NADH. In the first of
these reactions, glyceraldehyde-3-P dehydrogenase (G3PDH) catalyzes the NAD+-dependent
oxidation of G3P to 1,3-bisphosphoglycerate (1,3BPG) and NADH. The G3PDH
reaction is reversible, and the same enzyme catalyzes the reverse reaction
during gluconeogenesis.
Phosphoglycerate Kinase:
The high-energy phosphate of 1,3-BPG is used to form
ATP and 3-phosphoglycerate (3PG) by the enzyme phosphoglycerate kinase. Note
that this is the only reaction of glycolysis or gluconeogenesis that involves
ATP and yet is reversible under normal cell conditions. Associated with the phosphoglycerate
kinase pathway is an important reaction of erythrocytes, the formation of
2,3-bisphosphoglycerate, 2,3BPG (see Figure below) by the enzyme
bisphosphoglycerate mutase. 2,3BPG is an important regulator of hemoglobin's affinity for oxygen. Note that
2,3-bisphosphoglycerate phosphatase degrades 2,3BPG to 3-phosphoglycerate, a
normal intermediate of glycolysis. The 2,3BPG shunt thus operates with the
expenditure of 1 equivalent of ATP per triose passed through the shunt. The
process is not reversible under physiological conditions.
The pathway for 2,3-bisphosphoglycerate (2,3-BPG) synthesis within
erythrocytes. Synthesis of 2,3-BPG represents a major reaction pathway for the
consumption of glucose in erythrocytes. The synthesis of 2,3-BPG in
erythrocytes is critical for controlling hemoglobin affinity for oxygen. Note
that when glucose is oxidized by this pathway the erythrocyte loses the ability
to gain 2 moles of ATP from glycolytic oxidation of 1,3-BPG to
3-phosphoglycerate via the phosphoglycerate kinase reaction.
Phosphoglycerate Mutase and Enolase:
The remaining reactions of glycolysis are aimed at
converting the relatively low energy phosphoacyl-ester of 3PG to a high-energy
form and harvesting the phosphate as ATP. The 3PG is first converted to 2PG by
phosphoglycerate mutase and the 2PG conversion to phosphoenoylpyruvate (PEP) is
catalyzed by enolase
Pyruvate Kinase:
The final reaction of aerobic glycolysis
is catalyzed by the highly regulated enzyme pyruvate kinase (PK). In this
strongly exergonic reaction, the high-energy phosphate of PEP is conserved as
ATP. The loss of phosphate by PEP leads to the production of pyruvate in an
unstable enol form, which spontaneously tautomerizes to the more stable, keto
form of pyruvate. This reaction contributes a large proportion of the free
energy of hydrolysis of PEP.
Anaerobic
Glycolysis
http://www.youtube.com/watch?v=uCmNQQWlrc0&feature=related
Under aerobic conditions, pyruvate in
most cells is further metabolized via the TCA cycle. Under anaerobic conditions and
in erythrocytes under aerobic conditions, pyruvate is converted to lactate by
the enzyme lactate dehydrogenase (LDH), and the lactate is transported out of
the cell into the circulation. The conversion of pyruvate to lactate, under
anaerobic conditions, provides the cell with a mechanism for the oxidation of
NADH (produced during the G3PDH reaction) to NAD+; which occurs
during the LDH catalyzed reaction. This reduction is required since NAD+
is a necessary substrate for G3PDH, without which glycolysis will cease.
Normally, during aerobic glycolysis the electrons of cytoplasmic NADH are
transferred to mitochondrial carriers of the oxidative phosphorylation pathway
generating a continuous pool of cytoplasmic NAD+.
Aerobic glycolysis generates
substantially more ATP per mole of glucose oxidized than does anaerobic
glycolysis. The utility of anaerobic glycolysis, to a muscle cell when it needs
large amounts of energy, stems from the fact that the rate of ATP production
from glycolysis is approximately 100X faster than from oxidative
phosphorylation. During exertion muscle cells do not need to energize anabolic
reaction pathways. The requirement is to generate the maximum amount of ATP,
for muscle contraction, in the shortest time frame. This is why muscle cells
derive almost all of the ATP consumed during exertion from anaerobic
glycolysis.
The reactions catalyzed by hexokinase,
PFK-1 and PK all proceed with a relatively large free energy decrease. These
nonequilibrium reactions of glycolysis would be ideal candidates for regulation
of the flux through glycolysis. Indeed, in vitro studies have shown all
three enzymes to be allosterically controlled.
Regulation of hexokinase, however, is
not the major control point in glycolysis. This is due to the fact that large
amounts of G6P are derived from the breakdown of glycogen (the predominant
mechanism of carbohydrate entry into glycolysis in skeletal muscle) and,
therefore, the hexokinase reaction is not necessary. Regulation of PK is
important for reversing glycolysis when ATP is high in order to activate
gluconeogenesis. As such this enzyme catalyzed reaction is not a major control
point in glycolysis. The rate limiting step in glycolysis is the reaction
catalyzed by PFK-1.
PFK-1 is a tetrameric enzyme that
exist in two conformational states termed R and T that are in equilibrium. ATP is
both a substrate and an allosteric inhibitor of PFK-1. Each subunit has two ATP
binding sites, a substrate site and an inhibitor site. The substrate site binds
ATP equally well when the tetramer is in either conformation. The inhibitor
site binds ATP essentially only when the enzyme is in the T state. F6P is the
other substrate for PFK-1 and it also binds preferentially to the R state
enzyme. At high concentrations of ATP, the inhibitor site becomes occupied and
shifting the equilibrium of PFK-1 comformation to that of the T state
decreasing PFK-1's ability to bind F6P. The inhibition of PFK-1 by ATP is
overcome by AMP which binds to the R state of the enzyme and, therefore,
stabilizes the conformation of the enzyme capable of binding F6P. The most important
allosteric regulator of both glycolysis and gluconeogenesis is fructose 2,6-bisphosphate, F2,6BP,
which is not an intermediate in glycolysis or in gluconeogenesis.
Regulation of
glycolysis and gluconeogenesis by fructose
2,6-bisphosphate (F2,6BP). The major sites for regulation of glycolysis
and gluconeogenesis are the phosphofructokinase-1 (PFK-1) and
fructose-1,6-bisphosphatase (F-1,6-BPase) catalyzed reactions. PFK-2 is the
kinase activity and F-2,6-BPase is the phosphatase activity of the bi-functional
regulatory enzyme, phosphofructokinase-2/fructose-2,6-bisphosphatase. PKA is
cAMP-dependent protein kinase which phosphorylates PFK-2/F-2,6-BPase turning on
the phosphatase activity. (+ve) and (-ve) refer to positive and negative
activities, respectively.
The synthesis of F2,6BP is catalyzed
by the bifunctional enzyme phosphofructokinase-2/fructose-2,6-bisphosphatase
(PFK-2/F-2,6-BPase). In the nonphosphorylated form the enzyme is known as PFK-2
and serves to catalyze the synthesis of F2,6BP by phosphorylating fructose
6-phosphate. The result is that the activity of PFK-1 is greatly stimulated and
the activity of F-1,6-BPase is greatly inhibited.
Under conditions where PFK-2 is
active, fructose flow through the PFK-1/F-1,6-BPase reactions takes place in
the glycolytic direction, with a net production of F1,6BP. When the
bifunctional enzyme is phosphorylated it no longer exhibits kinase activity,
but a new active site hydrolyzes F2,6BP to F6P and inorganic phosphate. The
metabolic result of the phosphorylation of the bifunctional enzyme is that
allosteric stimulation of PFK-1 ceases, allosteric inhibition of F-1,6-BPase is
eliminated, and net flow of fructose through these two enzymes is
gluconeogenic, producing F6P and eventually glucose.
The interconversion of the
bifunctional enzyme is catalyzed by cAMP-dependent protein kinase (PKA), which
in turn is regulated by circulating peptide hormones. When blood glucose levels
drop, pancreatic insulin production falls, glucagon secretion is stimulated, and
circulating glucagon is highly increased. Hormones such as glucagon bind to
plasma membrane receptors on liver cells, activating membrane-localized
adenylate cyclase leading to an increase in the conversion of ATP to cAMP (see
diagram below). cAMP binds to the regulatory subunits of PKA, leading to
release and activation of the catalytic subunits. PKA phosphorylates numerous
enzymes, including the bifunctional PFK-2/F-2,6-BPase. Under these conditions
the liver stops consuming glucose and becomes metabolically gluconeogenic,
producing glucose to reestablish normoglycemia.
Representative pathway for the
activation of cAMP-dependent protein
kinase (PKA). In this example glucagon binds to its' cell-surface
receptor, thereby activating the receptor. Activation of the receptor is
coupled to the activation of a receptor-coupled G-protein (GTP-binding and
hydrolyzing protein) composed of 3 subunits. Upon activation the alpha subunit
dissociates and binds to and activates adenylate cyclase. Adenylate cylcase then
converts ATP to cyclic-AMP (cAMP). The cAMP thus produced then binds to the
regulatory subunits of PKA leading to dissociation of the associated catalytic
subunits. The catalytic subunits are inactive until dissociated from the
regulatory subunits. Once released the catalytic subunits of PKA phosphorylate
numerous substrate using ATP as the phosphate donor.
Regulation of glycolysis also occurs at the step
catalyzed by pyruvate kinase, (PK). The liver enzyme has been most studied in
vitro. This enzyme is inhibited by ATP and acetyl-CoA and is activated by
F1,6BP. The inhibition of PK by ATP is similar to the effect of ATP on PFK-1.
The binding of ATP to the inhibitor site reduces its affinity for PEP. The
liver enzyme is also controlled at the level of synthesis. Increased
carbohydrate ingestion induces the synthesis of PK resulting in elevated
cellular levels of the enzyme.
A number of PK isozymes have been described. The liver
isozyme (L-type), characteristic of a gluconeogenic tissue, is regulated via phosphorylation
by PKA, whereas the M-type isozyme found in brain, muscle, and other glucose
requiring tissue is unaffected by PKA. As a consequence of these differences,
blood glucose levels and associated hormones can regulate the balance of liver
gluconeogenesis and glycolysis while muscle metabolism remains unaffected.
In erythrocytes, the fetal PK isozyme has much greater
activity than the adult isozyme; as a result, fetal erythrocytes have
comparatively low concentrations of glycolytic intermediates. Because of the
low steady-state concentration of fetal 1,3BPG, the 2,3BPG shunt (see diagram
above) is greatly reduced in fetal cells and little 2,3BPG is formed. Since
2,3BPG is a negative effector of hemoglobin affinity for oxygen, fetal
erythrocytes have a higher oxygen affinity than maternal erythrocytes.
Therefore, transfer of oxygen from maternal hemoglobin to fetal hemoglobin is
favored, assuring the fetal oxygen supply. In the newborn, an erythrocyte
isozyme of the M-type with comparatively low PK activity displaces the fetal
type, resulting in an accumulation of glycolytic intermediates. The increased
1,3BPG levels activate the 2,3BPG shunt, producing 2,3BPG needed to regulate
oxygen binding to hemoglobin.
Genetic diseases of adult erythrocyte PK are known in
which the kinase is virtually inactive. The erythrocytes of affected
individuals have a greatly reduced capacity to make ATP and thus do not have
sufficient ATP to perform activities such as ion pumping and maintaining
osmotic balance. These erythrocytes have a short half-life, lyse readily, and
are responsible for some cases of hereditary
hemolytic anemia.
The liver PK isozyme is regulated by phosphorylation,
allosteric effectors, and modulation of gene expression. The major allosteric
effectors are F1,6BP, which stimulates PK activity by decreasing its Km(app)
for PEP, and for the negative effector, ATP. Expression of the liver PK gene is
strongly influenced by the quantity of carbohydrate in the diet, with
high-carbohydrate diets inducing up to 10-fold increases in PK concentration as
compared to low carbohydrate diets. Liver PK is phosphorylated and inhibited by
PKA, and thus it is under hormonal control similar to that described earlier
for PFK-2.
Muscle PK (M-type) is not regulated by the same
mechanisms as the liver enzyme. Extracellular conditions that lead to the
phosphorylation and inhibition of liver PK, such as low blood glucose and high
levels of circulating glucagon, do not inhibit the muscle enzyme. The result of
this differential regulation is that hormones such as glucagon and epinephrine
favor liver gluconeogenesis by inhibiting liver glycolysis, while at the same
time, muscle glycolysis can proceed in accord with needs directed by
intracellular conditions.
Pyruvate is the branch point molecule of glycolysis.
The ultimate fate of pyruvate depends on the oxidation state of the cell. In
the reaction catalyzed by G3PDH a molecule of NAD+ is reduced to
NADH. In order to maintain the re-dox state of the cell, this NADH must be
re-oxidized to NAD+. During aerobic glycolysis this occurs in the
mitochondrial electron transport chain generating ATP. Thus, during aerobic
glycolysis ATP is generated from oxidation of glucose directly at the PGK and
PK reactions as well as indirectly by re-oxidation of NADH in the oxidative phosphorylation pathway.
Additional NADH molecules are generated during the complete aerobic oxidation
of pyruvate in the TCA cycle. Pyruvate enters the TCA cycle in
the form of acetyl-CoA which is
the product of the pyruvate dehydrogenase reaction. The fate of pyruvate during
anaerobic glycolysis is reduction to lactate.
During anaerobic glycolysis, that period of time when
glycolysis is proceeding at a high rate (or in anaerobic organisms), the
oxidation of NADH occurs through the reduction of an organic substrate.
Erythrocytes and skeletal muscle (under conditions of exertion) derive all of
their ATP needs through anaerobic glycolysis. The large quantity of NADH
produced is oxidized by reducing pyruvate to lactate. This reaction is carried
out by lactate dehydrogenase, (LDH). The lactate produced during anaerobic
glycolysis diffuses from the tissues and is transproted to highly aerobic
tissues such as cardiac muscle and liver. The lactate is then oxidized to
pyruvate in these cells by LDH and the pyruvate is further oxidized in the TCA
cycle. If the energy level in these cells is high the carbons of pyruvate will
be diverted back to glucose via the gluconeogenesis pathway.
Mammalian cells contain two distinct types of LDH
subunits, termed M and H. Combinations of these different subunits generates
LDH isozymes with different characteristics. The H type subunit predominates in
aerobic tissues such as heart muscle (as the H4 tetramer) while the M subunit
predominates in anaerobic tissues such as skeletal muscle as the M4 tetramer).
H4 LDH has a low Km for pyruvate and also is inhibited by high
levels of pyruvate. The M4 LDH enzyme has a high Km for pyruvate and
is not inhibited by pyruvate. This suggsts that the H-type LDH is utilized for
oxidizing lactate to pyruvate and the M-type the reverse.
Ethanol Metabolism
Animal cells (primarily hepatocytes) contain the
cytosolic enzyme alcohol dehydrogenase (ADH) which oxidizes ethanol to
acetaldehyde. Acetaldehyde then enters the mitochondria where it is oxidized to
acetate by acetaldehyde dehydrogenase (AcDH).
Acetaldehyde forms adducts with proteins, nucleic
acids and other compounds, the results of which are the toxic side effects (the
hangover) that are associated
with alcohol consumption. The ADH and AcDH catalyzed reactions also leads to
the reduction of NAD+ to NADH. The metabolic effects of ethanol
intoxication stem from the actions of ADH and AcDH and the resultant cellular
imbalance in the NADH/NAD+. The NADH produced in the cytosol by ADH
must be reduced back to NAD+ via either the malate-aspartate shuttle or the glycerol-phosphate shuttle. Thus, the
ability of an individual to metabolize ethanol is dependent upon the capacity
of hepatocytes to carry out eother of these 2 shuttles, which in turn is
affected by the rate of the TCA cycle in the mitochondria whose rate of
function is being impacted by the NADH produced by the AcDH reaction. The
reduction in NAD+ impairs the flux of glucose through glycolysis at
the glyceraldehyde-3-phosphate dehydrogenase reaction, thereby limiting energy
production. Additionally, there is an increased rate of hepatic lactate
production due to the effect of increased NADH on direction of the hepatic
lactate dehydrogenase (LDH) reaction. This reverseral of the LDH reaction in
hepatocytes diverts pyruvate from gluconeogenesis leading to a reduction in the
capacity of the liver to deliver glucose to the blood.
In addition to the negative effects of the altered
NADH/NAD+ ratio on hepatic gluconeogenesis, fatty acid oxidation is
also reduced as this process requires NAD+ as a cofactor. In fact
the opposite is true, fatty acid synthesis is increased and there is an
increase in triacylglyceride production by the liver. In the mitocondria, the
production of acetate from acetaldehyde leads to increased levels of
acetyl-CoA. Since the increased generation of NADH also reduces the activity of
the TCA cycle, the acetyl-CoA is diverted to fatty acid synthesis. The
reduction in cytosolic NAD+ leads to reduced activity of
glycerol-3-phosphate dehydrogenase (in the glcerol 3-phosphate to DHAP
direction) resulting in increased levels of glycerol 3-phosphate which is the
backbone for the synthesis of the triacylglycerides. Both of these two events
lead to fatty acid deposition in the liver leading to fatty liver syndrome.
Regulation
of Blood Glucose Levels
If for no other reason, it is because
of the demands of the brain for oxidizable glucose that the human body
exquisitely regulates the level of glucose circulating in the blood. This level
is maintained in the range of 5mM.
Nearly all carbohydrates ingested in
the diet are converted to glucose following transport to the liver. Catabolism
of dietary or cellular proteins generates carbon atoms that can be utilized for
glucose synthesis via gluconeogenesis. Additionally, other
tissues besides the liver that incompletely oxidize glucose (predominantly
skeletal muscle and erythrocytes) provide lactate that can be converted to
glucose via gluconeogenesis.
Maintenance of blood glucose
homeostasis is of paramount importance to the survival of the human organism.
The predominant tissue responding to signals that indicate reduced or elevated
blood glucose levels is the liver. Indeed, one of the most important functions
of the liver is to produce glucose for the circulation. Both elevated and
reduced levels of blood glucose trigger hormonal responses to initiate pathways
designed to restore glucose homeostasis. Low blood glucose triggers release of glucagon from pancreatic -cells.
High blood glucose triggers release of insulin
from pancreatic -cells.
Additional signals, ACTH and growth
hormone, released from the pituitary act to increase blood glucose by
inhibiting uptake by extrahepatic tissues. Glucocorticoids also act to increase blood glucose levels by
inhibiting glucose uptake. Cortisol,
the major glucocorticoid released from the adrenal cortex, is secreted in
response to the increase in circulating ACTH. The adrenal medullary hormone, epinephrine, stimulates production of
glucose by activating glycogenolysis in response to stressful stimuli.
Glucagon binding to its' receptors on
the surface of liver cells triggers an increase in cAMP production leading to
an increased rate of glycogenolysis by activating glycogen
phosphorylase via the PKA-mediated cascade. This is the same response
hepatocytes have to epinephrine release. The resultant increased levels of G6P
in hepatocytes is hydrolyzed to free glucose, by glucose-6-phosphatase, which
then diffuses to the blood. The glucose enters extrahepatic cells where it is
re-phosphorylated by hexokinase. Since muscle and brain cells lack
glucose-6-phosphatase, the glucose-6-phosphate product of hexokinase is
retained and oxidized by these tissues.
In opposition to the cellular
responses to glucagon (and epinephrine on hepatocytes), insulin stimulates
extrahepatic uptake of glucose from the blood and inhibits glycogenolysis in
extrahepatic cells and conversely stimulates glycogen synthesis. As the glucose
enters hepatocytes it binds to and inhibits glycogen phosphorylase activity.
The binding of free glucose stimulates the de-phosphorylation of phosphorylase
thereby, inactivating it. Why is it that the glucose that enters hepatocytes is
not immediately phosphorylated and oxidized? Liver cells contain an isoform of
hexokinase called glucokinase. Glucokinase has a much lower affinity for
glucose than does hexokinase. Therefore, it is not fully active at the
physiological ranges of blood glucose. Additionally, glucokinase is not
inhibited by its product G6P, whereas, hexokinase is inhibited by G6P.
One major response of non-hepatic
tissues to insulin is the recruitment, to the cell surface, of glucose
transporter complexes. Glucose transporters comprise a family of five members, GLUT-1 to GLUT-5. GLUT-1 is
ubiquitously distributed in various tissues. GLUT-2 is found primarily in
intestine, kidney and liver. GLUT-3 is also found in the intestine and GLUT-
Hepatocytes, unlike most other cells,
are freely permeable to glucose and are, therefore, essentially unaffected by
the action of insulin at the level of increased glucose uptake. When blood
glucose levels are low the liver does not compete with other tissues for
glucose since the extrahepatic uptake of glucose is stimulated in response to
insulin. Conversely, when blood glucose levels are high extrahepatic needs are
satisfied and the liver takes up glucose for conversion into glycogen for future needs. Under conditions
of high blood glucose, liver glucose levels will be high and the activity of
glucokinase will be elevated. The G6P produced by glucokinase is rapidly
converted to G1P by phosphoglucomutase, where it can then be incorporated into
glycogen.
back to the top
Digestion & Absorption of Proteins &
Carbohydrates
Digestion and Absorption of Proteins
General Information:
1. Humans must ingest proteins, carbohydrates
and lipids to maintain tissue and organ functions.
2. Most of these nutrients
consist of large polymers that must be broken down before they can be made
available to the intestinal cells for transport.
3. Dietary proteins are cleaved
by hydrolases with specificity for the peptide bond (peptidases).
4. Endopeptidases (aka Proteases):
attack internal protein bonds liberating large peptide fragments.
Exopeptidases: cleave off one amino acid at a time from
the....
NH3+, aminopeptidases or COO- terminus,
carboxypeptidase.
5. Endo- and Exopeptidases work
in concert
The Big Picture:
Protein Digestion and Absorption
Gastric (Stomach) Digestion:
1. Gastric HCl is
responsible for the low pH <2 of gastric juice.
2. Gastric acid kills
microorganisms and denatures dietary proteins preparing them for
hydrolysis by proteases.
3. Gastric juices contain the acid
stable proteases of the pepsin family, which produce large
peptide fragments and some free amino acids.
4. Protein digestion at this
stage is partial, as the amino acids enter the duodenum, they trigger the
release of cholectystokinin-pancreozymin (CCK-PZ) into the bloodstream.
This release initiates the secretion
of protease zymogens from the pancreas and releases of enteropeptidase
in the gut.
Pancreatic Proteases:
1. The pancreatic juice is rich
in the proenzymes of endopeptidase and carboxypeptidases.
2. Enteropeptidase activates
pancreatic trypsinogen to trypsin.
3. Trypsin
autocatalytically activates more trypsinogen and other
proenzymes, liberating chymotrypsin, elastase and the carboxypeptidases
A and B.
Secretion and Activation of
Pancreatic Proteases:
Digestion at the
Brush Border (surface of intestinal
epithelial cells):
1. Since pancreatic juice does
not contain appreciable aminopeptidase activity, final digestion of di- and
small peptides depends on brush border enzymes.
2. The surface of intestinal
epithelial cells is rich in endopeptidases and aminopeptidases.
3. The end products of cell
surface digestion are free amino acids and di- and tripeptides.
Absorption:
1. Following digestion, amino
acids and small peptides are co-absorbed w/ sodium via group
specific amino acid or peptide transport systems.
2. These processes are carrier
mediated, discriminating between natural, L amino acids and D-amino
acids, require energy (from the Na+ gradient, Na-K ATPase)
and physiologic temperatures.
At least five brush border
transport systems exist:
1. neutral amino acids
(uncharged aliphatic and aromatic)
2. basic amino acids (Lys, Arg,
Cys, Cys-Cys)
3. acidic amino acids (Asp, Glu)
4. imino acids (Pro),
Hydroxyproline)
5. di- and tripeptides
Clinical Correlates:
1. Hartnup Disease:
Genetic defect in the neutral
amino acid transporter.
Symptoms: dermatitis due to
tryptophan malabsorption ("niacin" flush)
Consequences: not serious di-
and tripeptide absorption supply minimal amounts of dietarily essential neutral
amino acids.
2. Cystinuria:
Precursor to kidney stones
Symptoms: painful kidney stone
formation due to malabsoprtion of cystine (two disulfide linked cysteines)
3. Sprue:
Destruction and flattening of
the intestinal villi resulting in generalized malabsorption.
Causes: bacterial infection or
gluten (contained in certain grains such as wheat and barley) sensitivity.
Digestion and Absorption
of Carbohydrates
General Information:
1. Carbohydrates provide a major
component of the daily caloric requirement, ~40%.
2.Distinguish between mono-, di-
and polysaccharides.
Monosaccharides- do not need hydrolysis prior to absorption.
Disaccharides- require brush border enzymes.
Polysaccharides- require brush border enzymes, as well as, pancreatic
amylase and salivary amylase for digestion.
Starch:
Hydrolyzed by -amylase into Maltotriose, -Limit Dextrin, Maltose, Glucose
-1,4-glucosidic linkages (non-branching, amylose) and
branched chains -1,6 linkages (branch points, amylopectin)
-amylase:
Present in saliva and pancreatic
juice.
Specific for internal -1,4-glucosidic bonds.
Brush Border Carbohydrate Digestion:
Final hydrolysis of di- and oligosaccharides to
monosaccharides is carried out by -glucosidases
on the surface of the small intestine.
Monosaccharides are absorbed by carrier mediated
transport.
At least two types are known:
1. Na+monosaccharide transporter
2. Na+ independent, diffusion type
monosaccharide transport system
Undigested Carbohydrates:
1. Di-, oligo- and polysaccharides that are not
hydrolyzed by -amylase and/or brush border enzymes cannot be
absorbed.
2. These carbohydrates reach the lower tract of the
intestine which contains bacteria.
3. The bacteria utilize many of the remaining
carbohydrate, metabolizing them and producing by- products such as: hydrogen
gas, methane and carbon dioxide.
Carbohydrates
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Carbohydrates
are one of three macronutrients that provide the body with energy (protein
and fats being the other two). The chemical compounds in carbohydrates are
found in both simple and complex forms, and in order for the body to use
carbohydrates for energy, food must undergo digestion, absorption, and glycolysis.
It is recommended that 55 to 60 percent of caloric intake come from
carbohydrates.
Chemical Structure
Carbohydrates
are a main source of energy for the body and are made of carbon, hydrogen, and oxygen.
Chlorophyll in plants absorbs light energy from the sun. This energy is used in
the process of photosynthesis, which allows green plants to take in carbon
dioxide and release oxygen and allows for the production of carbohydrates. This
process converts the sun's light energy into a form of chemical energy useful
to humans. Plants transform carbon dioxide (CO2) from the air, water
(H2O) from the ground, and energy from the sun into oxygen (O2)
and carbohydrates (C6H12O6) (6 CO2 +
6 H2O + energy = C6H12O6 + 6 O2).
Most carbohydrates have a ratio of 1:2:1 of carbon, hydrogen, and oxygen,
respectively.
Humans
and other animals obtain carbohydrates by eating foods that contain them. In
order to use the energy contained in the carbohydrates, humans must metabolize,
or break down, the structure of the molecule in a process that is opposite that
of photosynthesis. It starts with the carbohydrate and oxygen and produces
carbon dioxide, water, and energy. The body utilizes the energy and water and
rids itself of the carbon dioxide.
Simple Carbohydrates
Simple
carbohydrates, or simple sugars, are composed of monosaccharide or disaccharide
units. Common monosaccharides (carbohydrates composed of single sugar units)
include glucose, fructose, and galactose. Glucose is the most common
type of sugar and the primary form of sugar that is stored in the body for
energy. It sometimes is referred to as blood sugar or dextrose and is of
particular importance to individuals who have diabetes or hypoglycemia.
Fructose, the primary sugar found in fruits, also is found in honey and
high-fructose corn syrup (in soft drinks) and is a major source of sugar in the
diet of Americans. Galactose is less likely than glucose or fructose to
be found in nature. Instead, it often combines with glucose to form the
disaccharide lactose, often referred to as milk sugar. Both fructose and
galactose are metabolized to glucose for use by the body.
Oligosaccharides
are carbohydrates made of two to ten monosaccharides. Those composed of two
sugars are specifically referred to as disaccharides, or double sugars. They contain
two monosaccharides bound by either an alpha bond or a beta bond. Alpha bonds
are digestible by the human body, whereas beta bonds are more difficult for the
body to break down.
There
are three particularly important disaccharides: sucrose, maltose, and
lactose. Sucrose is formed when glucose and fructose are held together by an
alpha bond. It is found in sugar cane or sugar beets and is refined to make
granulated table sugar. Varying
the degree of purification alters the
SUGAR
COMPARISON
|
Sugar |
Carbohydrate |
Monosaccharide
or disaccharide |
Additional
information |
|
Beet
sugar (cane sugar) |
Sucrose |
Disaccharide
(fructose and glucose) |
Similar to white and powdered sugar, but varied
degree of purification |
|
Brown
sugar |
Sucrose |
Disaccharide
(fructose and glucose) |
Similar to white and powdered sugar, but varied
degree of purification |
|
Corn
syrup |
Glucose |
Monosaccharide
|
|
|
Fruit
sugar |
Fructose |
Monosaccharide
|
Very
sweet |
|
High-fructose
corn syrup |
Fructose |
Monosaccharide
|
Very sweet and inexpensive |
|
Honey |
Fructose
and glucose |
Monosaccharides
|
|
|
Malt
sugar |
Maltose |
Disaccharide
(glucose and glucose) |
Formed by the hydrolysis of starch, but sweeter
than starch |
|
Maple
syrup |
Sucrose |
Disaccharide
(fructose and glucose) |
|
|
Milk
sugar |
Lactose |
Disaccharide
(glucose and galactose) |
Made in mammary glands of most lactating
animals |
|
Powdered
sugar |
Sucrose |
Disaccharide
(fructose and glucose) |
Similar to white and brown sugar, but varied
degree of purification |
|
White
sugar |
Sucrose |
Disaccharide
(fructose and glucose) |
Similar to brown and powdered sugar, but varied
degree of purification |
|
SOURCE: Mahan and Escott-Stump, 2000;
Northwestern University; Sizer and Whitney, 1997; and Wardlaw and Kessel,
2002. |
|||
final
product, but white, brown, and powdered sugars all are forms of sucrose. Maltose,
or malt sugar, is composed of two glucose units linked by an alpha bond. It is
produced from the chemical decomposition of starch, which occurs during the
germination of seeds and the production of alcohol. Lactose is a combination of
glucose and galactose. Because it contains a beta bond, it is hard for some
individuals to digest in large quantities. Effective digestion requires
sufficient amounts of the enzyme lactase.
Complex Carbohydrates
Complex carbohydrates, or polysaccharides, are
composed of simple sugar units in long chains called polymers. Three
polysaccharides are of particular importance in human nutrition: starch,
glycogen, and dietary fiber.
Starch and glycogen are digestible forms of complex
carbohydrates made of strands of glucose units linked by alpha bonds. Starch,
often contained in seeds, is the form in which plants store energy, and there
are two types: amylose and amylopectin. Starch represents the main type of
digestible complex carbohydrate. Humans use an enzyme to break down the bonds
linking glucose units, thereby releasing the sugar to be absorbed into the
bloodstream. At that point, the body can distribute glucose to areas that need
energy, or it can store the glucose in the form of glycogen.
Glycogen is the polysaccharide used to store energy in
animals, including humans. Like starch, glycogen is made up of chains of
glucose linked by alpha bonds; but glycogen chains are more highly branched
than starch. It is this highly branched structure that allows the bonds to be
more quickly broken down by enzymes in the body. The primary storage sites for
glycogen in the human body are the liver and the muscles.
Another type of complex carbohydrate is dietary fiber.
In general, dietary fiber is considered to be polysaccharides that have not
been digested at the point of entry into the large intestine. Fiber contains
sugars linked by bonds that cannot be broken down by human enzymes, and are
therefore
![Pastas and whole-grain breads contain complex carbohydrates, which are long strands of glucose molecules. Nutritionists recommend that 55–60 percent of calories come from carbohydrates, and especially complex carbohydrates. [Photograph by James Noble. Corbis. Reproduced by permission.]](03%20Anaerobic%20and%20aerobic%20oxidation%20of%20glucose.files/image032.jpg)
Pastas and whole-grain breads contain
complex carbohydrates, which are long strands of glucose molecules.
Nutritionists recommend that 55–60 percent of calories come from carbohydrates,
and especially complex carbohydrates.
[Photograph by James Noble. Corbis.
Reproduced by permission.]
labeled as indigestible. Because of
this, most fibers do not provide energy for the body. Fiber is derived from
plant sources and contains polysaccharides such as cellulose,
hemicellulose, pectin, gums, mucilages, and lignins.
The indigestible fibers cellulose, hemicellulose, and
lignin make up the structural part of plants and are classified as insoluble
fiber because they usually do not dissolve in water. Cellulose is a nonstarch
carbohydrate polymer made of a straight chain of glucose molecules
linked by beta bonds and can be found in whole-wheat flour, bran, and
vegetables. Hemicellulose is a nonstarch carbohydrate polymer made of glucose,
galactose, xylose, and other monosaccharides; it can be found in bran and whole
grains. Lignin, a noncarbohydrate polymer containing alcohols and acids, is a
woody fiber found in wheat bran and the seeds of fruits and vegetables.
In contrast, pectins, mucilages, and gums are
classified as soluble fibers because they dissolve or swell in water. They are
not broken down by human enzymes, but instead can be metabolized (or fermented)
by bacteria present in the large intestine. Pectin is a fiber made of
galacturonic acid and other monosaccharides. Because it absorbs water and forms
a gel, it is often used in jams and jellies. Sources of pectin include citrus
fruits, apples, strawberries, and carrots. Mucilages and gums are similar in
structure. Mucilages are dietary fibers that contain galactose, manose, and
other monosaccharides; and gums are dietary fibers that contain galactose,
glucuronic acid, and other monosaccharides. Sources of gums include oats, legumes,
guar, and barley.
Digestion and Absorption
Carbohydrates
must be digested and absorbed in order to transform them into energy that can
be used by the body. Food preparation often aids in the digestion process. When
starches are heated, they swell and become easier for the body to break down.
In the mouth, the enzyme amylase, which is contained in saliva, mixes with food
products and breaks some starches into smaller units. However, once the
carbohydrates reach the acidic environment of the stomach, the amylase is
inactivated. After the carbohydrates have passed through the stomach and into
the small intestine, key digestive enzymes are secreted from the pancreas and the
small intestine where most digestion and absorption occurs. Pancreatic amylase
breaks starch into disaccharides and small polysaccharides, and enzymes from
the cells of the small-intestinal wall break any remaining disaccharides into
their monosaccharide components. Dietary fiber is not digested by the small
intestine; instead, it passes to the colon unchanged.
Sugars
such as galactose, glucose, and fructose that are found naturally in foods or
are produced by the breakdown of polysaccharides enter into absorptive
intestinal cells. After absorption, they are transported to the liver where
galactose and fructose are converted to glucose and released into the
bloodstream. The glucose may be sent directly to organs that need energy, it
may be transformed into glycogen (in a process called glycogenesis) for storage
in the liver or muscles, or it may be converted to and stored as fat.
Glycolysis
http://www.youtube.com/watch?v=O5eMW4b29rg&feature=related
The
molecular bonds in food products do not yield high amounts of energy when
broken down. Therefore, the energy contained in food is released within cells
and stored in the form of adenosine triphosphate (ATP), a high-energy compound
created by cellular energy-production systems. Carbohydrates are metabolized
and used to produce ATP molecules through a process called glycolysis.
Glycolysis
breaks down glucose or glycogen into pyruvic acid through enzymatic
reactions within the cytoplasm of the cells. The process results in the
formation of three molecules of ATP (two, if the starting product was glucose).
Without the presence of oxygen, pyruvic acid is changed to lactic acid,
and the energy-production process ends. However, in the presence of oxygen,
larger amounts of ATP can be produced. In that situation, pyruvic acid is
transformed into a chemical compound called acetyle coenzyme A, a
compound that begins a complex series of reactions in the Krebs Cycle
and the electron transport system. The end result is a net gain of up to
thirty-nine molecules of ATP from one molecule of glycogen (thirty-eight
molecules of ATP if glucose was used). Thus, through certain systems, glucose
can be used very efficiently in the production of energy for the body.
Recommended Intake
At
times, carbohydrates have been incorrectly labeled as "fattening."
Evidence actually supports the consumption of more, rather than less, starchy
foods. Carbohydrates have four calories per gram, while dietary fats
contribute nine per gram, so diets high in complex carbohydrates are likely to
provide fewer calories than diets high in fat. Recommendations are for 55 to 60
percent of total calories to come from carbohydrates (approximately 275 to
Low-Carb Diets
Low-carbohydrate
diets, such as the Atkins and South Beach diets, are based on the proposition
that it's not fat that makes you fat. Allowing dieters to eat steak, butter,
eggs, bacon, and other high-fat foods, these diets instead outlaw starches and
refined carbohydrates on the theory that they are metabolized so quickly that
they lead to hunger and overeating. This theory, which was first popularized in
the nineteenth century, came under scathing criticism from the medical
establishment during the early 1970s when Dr. Robert Atkins published the
phenomenally popular low-carb diet bearing his name. According to the American
Medical Association (AMA), the Atkins diet was a "bizarre regimen"
that advocated "an unlimited intake of saturated fats and cholesterol-rich
foods" and therefore presented a considerable risk of heart disease. Most
doctors recommended instead a diet low in fat and high in carbohydrates, with
plenty of grains, fruits, and vegetables and limited red meat or dairy products.
This became the received wisdom during the 1980s, at the same time that the
U.S. waistline began to expand precipitously. As dieters found that weight loss
was difficult to maintain on a low-fat diet, low-carb diets regained
popularity—with as many as 30 million people trying a low-carb diet in 2003.
Several small-scale studies began to suggest that a low-carb diet may indeed be
effective and may not have the deleterious effects its detractors have claimed;
other research found that any benefits of a low-carb diet are short-lived, and
that the negative effects will take decades to become evident. The National
Institutes of Health has pledged $2.5 million for a five-year study of the
Atkins diet with 360 subjects. While the results of this and other large-scale studies
are awaited, many researchers stress that the key issue in maintaining a
healthy weight is the number of calories consumed, not the type of calories.
The National Academy of Sciences recommends that adults obtain 45 to 65 percent
of their calories from carbohydrates, 20 to 35 percent from fat, and 10 to 35
percent from protein.
—Paula
Kepos
It
is important to consume a minimum amount of carbohydrates to prevent ketosis,
a condition resulting from the breakdown of fat for energy in the absence of
carbohydrates. In this situation, products of fat breakdown, called ketone
bodies, build up in the blood and alter normal pH balance. This can be
particularly harmful to a fetus. To avoid ketosis, daily carbohydrate intake
should include a minimum of 50 to
Exchange System
The
exchange system is composed of lists that describe carbohydrate, fat, and
protein content, as well as caloric content, for designated portions of
specific foods. This system takes into account the presence of more than one
type of nutrient in any given food. Exchange lists are especially useful for
individuals who require careful diet planning, such as those who monitor intake
of calories or certain nutrients. It is particularly useful for diabetics, for
whom carbohydrate intake must be carefully controlled, and was originally
developed for planning diabetic diets.
Diabetes, Carbohydrate-Modified Diets, and
Carbohydrate Counting
Diabetes
is a condition that alters the way the body handles carbohydrates. In terms of
diet modifications, diabetics can control blood sugar levels by appropriately
managing the carbohydrates, proteins, and fats in their meals. The amount of
carbohydrates, not necessarily the source, is the primary issue. Blood glucose
levels after a meal can be related to the process of food preparation, the
amount of food eaten, fat intake, sugar absorption, and the combination of
foods in the meal or snack.
One
method of monitoring carbohydrate levels—carbohydrate counting—assigns a
certain number of carbohydrate grams or exchanges to specific foods.
Calculations are used to determine insulin need, resulting in better
control of blood glucose levels with a larger variety of foods. Overall,
diabetic diets can include moderate amounts of sugar, as long as they are
carefully monitored.
Glycolysis (detailed)
Nomenclature of carbohydrates - the
naming of carbohydrates - much more information than most of us need
1. Glucose - a monosaccharide -
what you measure in your blood.
The chemical formula for glucose
is C6H12O6.
2. Sucrose - a disaccharide -
table sugar. Is made of one molecule of glucose and one fructose.
3. Starch - amylose and
amylopectin - a polysaccharide - potatoes.
Amylose is a straight chain of
glucose molecules linked together.
Amylopectin is a branched chain
of glucose molecules.
4. Glycolysis is the breakdown of
glucose to release its energy in the form of ATP.
Carbohydrate
metabolism - a slide
presentation from the
more chemistry than most people
will want.
GLYCOGEN
METABOLISM
Glycogen:
Glycogen is the storage form of glucose in animals and
humans which is analogous to the starch in plants. Glycogen is synthesized and
stored mainly in the liver and the muscles. Structurally, glycogen is very similar
to amylopectin with alpha acetal linkages, however, it has even more branching
and more glucose units are present than in amylopectin. Various samples of
glycogen have been measured at 1,700-600,000 units of glucose.
The
structure of glycogen consists of long polymer chains of glucose units
connected by an alpha acetal linkage. The graphic on the left shows a
very small portion of a glycogen chain. All of the monomer units are
alpha-D-glucose, and all the alpha acetal links connect C # 1 of one glucose to
C # 4 of the next glucose.
The
branches are formed by linking C # 1 to a C # 6 through an acetal linkages. In
glycogen, the branches occur at intervals of 8-10 glucose units, while in
amylopectin the branches are separated by 12-20 glucose units.
Acetal Functional Group:
Carbon # 1 is called the anomeric carbon and is
the center of an acetal functional group. A carbon that has two ether oxygens
attached is an acetal.
The Alpha position is defined as the ether
oxygen being on the opposite side of the ring as the C #
Starch vs. Glycogen:
Plants make starch and cellulose through the
photosynthesis processes. Animals and human in turn eat plant materials and
products. Digestion is a process of hydrolysis where the starch is broken
ultimately into the various monosaccharides. A major product is of course
glucose which can be used immediately for metabolism to make energy. The
glucose that is not used immediately is converted in the liver and muscles into
glycogen for storage by the process of glycogenesis. Any glucose in excess of
the needs for energy and storage as glycogen is converted to fat.
http://www.youtube.com/watch?v=oBL0OC3IavI
Start with G-6-P, again note that
this molecule is at a metabolic crossroads. First convert to G-1-P using Phosphoglucomutase:
This reaction is very much like PGA
Mutase, requiring the bis phosphorylated intermediate to form and to
regenerate the phosphorylated enzyme intermediate. Again a separate
"support" enzyme, Phosphoglucokinase, is required to form the
intermediate, this time using ATP as the energy source:
Note that this reaction is easily
reversible, though it favors G-6-P.
UDP-glucose pyrophosphorylase,
which catalyzes the next reaction, has a near zero DG° ':
It is driven to completion by the hydrolysis of the PPi
to 2 Pi by Pyrophosphatase with a DG° ' of about -32 kJ
(approx. one ATP's worth of energy).
Finally glycogen is synthesized with Glycogen
Synthase:
UDPGlucose + (glucose)n
Æ UDP + (glucose)n+1
This reaction is favored by a DG° ' of about 12 kcal,
thus the overall synthesis of glycogen from G-1-P is favored by a standard free
energy of about 40 kJ. Note that the glucose is added to the non-reducing end
of a glycogen strand, and that there is a net investment of 2 ATP equivalents
per glucose (ATP to ADP and UTP to UDP, regenerated with ATP to ADP). Note also
that glycogen synthase requires a 'primer.' That is it needs to have a glycogen
chain to add on to. What happens then in new cells to make now glycogen
granules? Can use a special primer protein (glycogenin). Thus glycogen granules
have a protein core.
These reactions will give linear
glycogen strands, additional reactions are required to produce branching. Branching
enzyme [amylo-a-(1,4) to a-(1,6)-transglycosylase] transfers a block of
residues from the end of one chain to another chain making a 1,6-linkage
(cannot be closer than 4 residues to a previous branch). (For efficient release
of glucose residues it has been determined that the optimum branching pattern
is a new branch every 13 residues, with two branchs per strand.)
Glycogen is broken down using Phosphorylase to
phosphorylize off glucose residues:
(glucose)n + Pi
Æ (glucose)n-1 + G-1-P
Note that no ATP is required to recover Glucose
phosphate from glycogen. This is a major advantage in anaerobic tissues, get one
more ATP/glucose (3 instead of 2!). [Phosphorylase was originally thought to be
the synthetic as well as breakdown enzyme since the reaction is readily
reversible in vitro. However it was found that folks lacking this enzyme
- McArdle's disease - can still make glycogen, though they can't break it
down.]
Glycogen synthesis and degradation
occurs in the liver cells. It is here that the hormone insulin (the
primary hormone responsible for converting glucose to glycogen) acts to lower
blood glucose concentration. Insulin stimulates glycogen synthesis;
thereby, inhibiting glycogen degradation as shown in the figure. 3
Crystal structure of glycogen synthase:
homologous enzymes catalyze glycogen synthesis and degradation
Alejandro Buschiazzo, Juan E Ugalde,
Marcelo E Guerin, William Shepard, Rodolfo A Ugalde
and Pedro M Alzari
Figure 6
Molecular surface representation of the GS core,
showing the equivalent position of the arginine clusters in the mammalian/yeast
(GT3) allosteric site (in red) with respect to the active center. Assuming an
extended main-chain conformation, approximate distances are shown for two
relevant phosphorylation sites, one in the N-terminal (2a) and the other in the
C-terminal (3a) extensions of GT3 enzymes.
2. Liver - excess glycose production - gluconeogenesis
and glycogenolysis
In order to provide glucose for vital
functions such as the metabolism of RBC's and the CNS during periods of fasting
(greater than about 8 hrs after food absorption in humans), the body needs a
way to synthesis glucose from precursors such as pyruvate and amino acids. This
process is referred to as gluconeogenesis. It occurs in the liver and in
kidney. Most of Glycolysis can be used in this process since most glycolytic
enzymes are reversible. However three irreversible enzymes must be bypassed in gluconeogenesis vs.
glycolysis: Hexokinase, Phosphofructokinase,
and Pyruvate kinase. Phosphofructokinase, and/or hexokinase must also be
bypassed in converting other hexoses to glucose.
Let's
begin with pyruvate. How is pyruvate converted to PEP without using the
pyruvate kinase reaction? Formally, pyruvate is first converted to
oxaloacetate, which is in turn converted to PEP. In the first reaction of this
process Pyruvate carboxylase adds carbon dioxide to pyruvate with the
expenditure of one ATP equivalent of energy. Biotin, a carboxyl-group transfer
cofactor in animals, is required by this enzyme:
The reaction takes place in two parts
on two different sub-sites on the enzyme. In the first part biotin attacks
bicarbonate with a simultaneous attack/hydrolysis by bicarbonate on ATP,
resulting in the release of ADP and inorganic phosphate (note the coupling by
the enzyme of independent processes in this reaction):
Note that the 14 Angstrom arm of
biocytin allows biotin to move between the two sites, in this case carrying the
activated carboxyl group. In the second site a pyruvate carbanion then attacks
the activated carboxyl group, regenerating the biotin cofactor and releasing
oxaloacetate:
Investigation
of mechanisms of metabolism hormonal regulation and significance in medical
practice.
Investigation
of mechanisms of metabolism hormonal regulation and significance in medical
practice.
Insulin. Chemical structure: protein. Insulin
is formed in b-cells of Langerhans islets
(specialized endocrine regions of the
pancreas).
Proinsulin is the biosynthetic precursor of insulin.
Effect of insulin on
carbohydrate metabolism:
-
increases
the permeability of cell membranes for glucose;
-
activates
the first enzyme of glycolysis - glucokinase and prevent the inactivation of
hexokinase;
-
activates
some enzymes of Krebs cycle (citrate synthase);
-
activates
the pentose phosphate cycle;
-
activates
glycogen synthetase;
-
activates
pyruvate dehydrogenase and a-ketoglutarate dehydrogenase;
-
inhibits
the gluconeogenesis;
-
inhibits the
decomposition of glycogen.
Effect of insulin on protein
metabolism:
-
increases
the permeability of cell membranes for amino acids;
-
activates
synthesis of proteins and nucleic acids;
-
inhibits
the gluconeogenesis.
Effect of insulin on lipid
metabolism:
-
enhances
the synthesis of lipids;
-
promotes
the lipid storage activating the carbohydrate decomposition;
-
inhibits
the gluconeogenesis.
Effect of insulin on mineral
metabolism:
-
activates
Na+, K+-ATP-ase (transition of K into the cells and Na
from the cells).
Target tissue for insulin - liver, muscles and lipid
tissue.
The release of insulin from
pancreas depends on the glucose concentration in the blood. Some other
hormones, sympathetic and parasympathetic nervous system also can influence on
the rate of insulin secretion.
The deficiency of insulin
causes diabetes mellitus.
Insulin is destroyed in the organism
by the enzyme insulinase that is
produced by liver.
Insulin
Insulin crystals
Other names: insulin
Taxa expressing: Homo sapiens; homologs: in metazoan
taxa from invertebrates to
Antagonists: glucagon, steroids, most stress hormomes
http://www.youtube.com/watch?v=X0ezy1t6N08&feature=related
http://www.youtube.com/watch?v=BfZks1SjStA
Insulin (from Latin insula,
"island", as it is produced in the Islets of Langerhans in the
pancreas) is a polypeptide hormone that regulates carbohydrate metabolism.
Apart from being the primary agent in carbohydrate homeostasis, it has effects
on fat metabolism and it changes the liver's activity in storing or releasing
glucose and in processing blood lipids, and in other tissues such as fat and muscle.
The amount of insulin in circulation has extremely widespread effects
throughout the body.
Insulin is used
medically to treat some forms of diabetes mellitus. Patients with type 1
diabetes mellitus depend on external insulin (most commonly injected subcutaneously)
for their survival because of an absolute deficiency of the hormone. Patients
with type 2 diabetes mellitus have insulin resistance, relatively low insulin
production, or both; some type 2 diabetics eventually require insulin when
other medications become insufficient in controlling blood glucose levels.
Insulin's structure varies slightly
between species of animal. Insulin from animal sources differs somewhat in
regulatory function strength (ie, in carbohydrate metabolism) in humans because
of those variations. Porcine (pig) insulin is especially close to the human
version.
Discovery and characterization
In 1869 Paul Langerhans, a medical
student in Berlin, was studying the structure of the pancreas (the jelly-like
gland behind the stomach) under a microscope when he identified some previously
un-noticed tissue clumps scattered throughout the bulk of the pancreas. The
function of the "little heaps of cells," later known as the Islets of
Langerhans, was unknown, but Edouard Laguesse later suggested that they might
produce secretions that play a regulatory role in digestion.
In 1889, the Polish-German physician
Oscar Minkowski in collaboration with Joseph von Mehring removed the pancreas
from a healthy dog to test its assumed role in digestion. Several days after
the dog's pancreas was removed, Minkowski's animal keeper noticed a swarm of
flies feeding on the dog's urine. On testing the urine they found that there
was sugar in the dog's urine, establishing for the first time a relationship
between the pancreas and diabetes. In 1901, another major step was
taken by Eugene Opie, when he clearly established the
link between the Islets of Langerhans and diabetes: Diabetes mellitus ... is
caused by destruction of the islets of Langerhans and occurs only when these
bodies are in part or wholly destroyed. Before his work, the link between the
pancreas and diabetes was clear, but not the specific role of the islets.
The structure of insulin.
The left side is a space-filling model of the
insulin monomer, believed to be biologically active. Carbon is green, hydrogen
white, oxygen red, and nitrogen blue. On the right side is a cartoon of the
insulin hexamer, believed to be the stored form. A monomer unit is highlighted
with the A chain in blue and the B chain in cyan.
Yellow
denotes disulfide bonds, and magenta spheres are zinc ions.Over the next two
decades, several attempts were made to isolate whatever it was the islets
produced as a potential treatment. In 1906 George Ludwig Zuelzer was partially
successful treating dogs with pancreatic extract but was unable to continue his
work. Between 1911 and 1912, E.L. Scott at the University of Chicago used
aqueous pancreatic extracts and noted a slight diminution of glycosuria but was
unable to convince his director of his work's value; it was shut down. Israel
Kleiner demonstrated similar effects at Rockefeller University in 1919, but his
work was interrupted by World War I and he did not return to it. Nicolae
Paulescu, a professor of physiology at the University of Medicine and Pharmacy
in Bucharest, published similar work in 1921 that had been carried out in
France. Use of his techniques was patented in Romania, though no clinical use
resulted. It has been argued ever since that he is the rightful discoverer.
In October 1920, Frederick Banting
was reading one of Minkowski's papers and concluded that it is the very
digestive secretions that Minkowski had originally studied that were breaking
down the islet secretion(s), thereby making it impossible to extract
successfully. He jotted a note to himself Ligate pancreatic ducts of the dog.
Keep dogs alive till acini degenerate leaving islets. Try to isolate internal
secretion of these and relieve glycosurea.
The idea was that the
pancreas's internal secretion, which supposedly regulates sugar in the
bloodstream, might hold the key to the treatment of diabetes.
He travelled to Toronto to meet with
J.J.R. Macleod, who was not entirely impressed with his idea – so many before
him had tried and failed. Nevertheless, he supplied Banting with a lab at the
University, an assistant (medical student Charles Best), and 10 dogs, then left
on vacation during the summer of 1921. Their method was tying a ligature
(string) around the pancreatic duct, and, when examined several weeks later,
the pancreatic digestive cells had died and been absorbed by the immune system,
leaving thousands of islets. They then isolated an extract from these islets,
producing what they called isletin (what we now know as insulin), and tested
this extract on the dogs. Banting and Best were then able to keep a
pancreatectomized dog alive all summer because the extract lowered the level of
sugar in the blood.
Computer-generated image of
insulin hexamers highlighting the threefold symmetry, the zinc ions holding it
together, and the histidine residues involved in zinc binding.Macleod saw the
value of the research on his return but demanded a re-run to prove the method
actually worked. Several weeks later it was clear the second run was also a
success, and he helped publish their results privately in Toronto that
November. However, they needed six weeks to extract the isletin, which forced
considerable delays. Banting suggested that they try to use fetal calf pancreas,
which
had not yet developed digestive glands; he was
relieved to find that this method worked well. With the supply problem solved,
the next major effort was to purify the extract. In December 1921, Macleod
invited the biochemist James Collip to help with this task, and, within a
month, the team felt ready for a clinical test.
On January 11, 1922, Leonard Thompson, a 14-year-old diabetic who lay
dying at the Toronto General Hospital, was given the first injection of
insulin. However, the extract was so impure that Thompson suffered a severe
allergic reaction, and further injections were canceled. Over the next 12 days,
Collip worked day and night to improve the ox-pancreas extract, and a second
dose injected on the 23rd. This was completely successful, not only in not
having obvious side-effects, but in completely eliminating the glycosuria sign
of diabetes. However, Banting and Best never worked well with Collip, regarding
him as something of an interloper, and Collip left the project soon after.
The exact sequence of amino
acids comprising the insulin molecule, the so-called primary structure, was
determined by British molecular biologist Frederick Sanger. It was the first
protein to have its sequence be determined. He was awarded the 1958 Nobel Prize
in Chemistry for this work.
In 1969, after decades of work, Dorothy Crowfoot
Hodgkin determined the spatial conformation of the molecule, the so-called
tertiary structure, by means of X-ray diffraction studies. She had been awarded
a Nobel Prize in Chemistry in 1964 for the development of crystallography.
Rosalyn Sussman Yalow received the 1977 Nobel Prize in
Medicine for the development of the radioimmunoassay for insulin.
Insulin undergoes extensive posttranslational
modification along the production pathway. Production and secretion are largely
independent; prepared insulin is stored awaiting secretion. Both C-peptide and
mature insulin are biologically active. Cell components and proteins in this
image are not to scale.
Within vertebrates, the similarity
of insulins is very close. Bovine insulin differs from human in only three
amino acid residues, and porcine insulin in one. Even insulin from some species
of fish is similar enough to human to be effective in humans. The C-peptide of
proinsulin (discussed later), however, is very divergent from species to
species.
![fitness_diabetes[11]](03%20Anaerobic%20and%20aerobic%20oxidation%20of%20glucose.files/image322.jpg)
In mammals, insulin is synthesized in the pancreas
within the beta cells (β-cells) of
the islets of Langerhans.
One to three million islets of
Langerhans (pancreatic islets) form the endocrine part of the pancreas, which
is primarily an exocrine gland. The endocrine portion only accounts for 2% of
the total mass of the pancreas. Within the islets of Langerhans, beta cells
constitute 60–80% of all the cells.
In beta cells, insulin is
synthesized from the proinsulin precursor molecule by the action of proteolytic
enzymes, known as prohormone convertases (PC1 and PC2), as well as the
exoprotease carboxypeptidase E. These modifications of proinsulin remove the
center portion of the molecule, or C-peptide, from the C- and N- terminal ends
of the proinsulin. The remaining polypeptides (51 amino acids in total), the B-
and A- chains, are bound together by disulfide bonds. Confusingly, the primary
sequence of proinsulin goes in the order "B-C-A", since B and A
chains were identified on the basis of mass, and the C peptide was discovered
after the others.
Effect of insulin on glucose
uptake and metabolism. Insulin binds to its receptor which in turn starts many protein activation
cascades. These include: translocation of Glut-4 transporter to the plasma
membrane and influx of glucose, glycogen synthesis, glycolysis and fatty acid synthesis.
Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor which in turn starts many protein activation
cascades. These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose, glycogen synthesis , glycolysis and fatty acid synthesis.
Control of cellular intake of certain substances, most
prominently glucose in muscle and adipose tissue (about ⅔ of body cells).
Increase of DNA replication and protein synthesis via
control of amino acid uptake.
Modification of the activity of numerous enzymes
(allosteric effect).
The actions of insulin on cells include:
http://www.youtube.com/watch?v=cTDWZp4sLuU&feature=related
Increased glycogen synthesis – insulin forces storage
of glucose in liver (and muscle) cells in the form of glycogen; lowered levels
of insulin cause liver cells to convert glycogen to glucose and excrete it into
the blood.
This is the clinical action of
insulin which is directly useful in reducing high blood glucose levels as in
diabetes.
Increased fatty acid synthesis
– insulin forces fat cells to take in blood lipids which are converted to
triglycerides; lack of insulin causes the reverse.
Increased esterification of fatty acids – forces
adipose tissue to make fats (ie, triglycerides) from fatty acid esters; lack of
insulin causes the reverse.
Decreased proteinolysis – forces reduction of protein
degradation; lack of insulin increases protein degradation.
Decreased lipolysis – forces reduction in conversion
of fat cell lipid stores into blood fatty acids; lack of insulin causes the
reverse.
Decreased gluconeogenesis – decreases production of
glucose from various substrates in liver; lack of insulin causes glucose
production from assorted substrates in the liver and elsewhere.
Increased amino
acid uptake – forces cells to absorb
circulating amino acids; lack of insulin inhibits absorption.
Increased
potassium uptake – forces cells to absorb
serum potassium; lack of insulin inhibits absorption.
Arterial muscle
tone – forces arterial wall muscle to
relax, increasing blood flow, especially in micro arteries; lack of insulin
reduces flow by allowing these muscles to contract.
Regulatory action on blood glucose
![400px-Insulin_glucose_metabolism[1]](03%20Anaerobic%20and%20aerobic%20oxidation%20of%20glucose.files/image329.jpg)
human blood glucose levels normally
remain within a narrow range. In most humans this varies from about 70 mg/dl to
perhaps 110 mg/dl (3.9 to 6.1 mmol/litre) except shortly after eating when the
blood glucose level rises temporarily. This homeostatic effect is the result of
many factors, of which hormone regulation is the most important.
It is usually a surprise to realize
how little glucose is actually maintained in the blood, and body fluids. The
control mechanism works on very small quantities. In a healthy adult male of
growth hormone men). A more familiar comparison may
help --
There are two types of
mutually antagonistic metabolic hormones affecting blood glucose levels: catabolic hormones (such as glucagon, growth
hormone, and catecholamines), which increase blood glucose and one anabolic
hormone (insulin), which decreases blood glucose
Mechanisms
which restore satisfactory blood glucose levels after hypoglycemia must be
quick, and effective, because of the immediate serious consequences of
insufficient glucose (in the extreme, coma, less immediately dangerously,
confusion or unsteadiness, amongst many other effects). This is because, at
least in the short term, it is far more dangerous to have too little glucose in
the blood than too much. In healthy individuals these mechanisms are indeed
generally efficient, and
symptomatic hypoglycemia is generally only found in diabetics using insulin or
other pharmacologic treatment. Such hypoglycemic episodes vary greatly between
persons and from time to time, both in severity and swiftness of onset. In
severe cases prompt medical assistance is essential, as damage (to brain and
other tissues) and even death will result from sufficiently low blood glucose
levels.
Diabetic Retinopathy
Diabetes causes an excessive
amount of glucose to remain in the blood stream which may cause damage to the
blood vessels. Within the eye the damaged vessels may leak blood and fluid into
the surrounding tissues and cause vision problems.
Mechanism of
glucose dependent insulin releaseBeta cells in the islets of Langerhans are
sensitive to variations in blood glucose levels through the following mechanism
(see figure to the right):
Mechanism of glucose dependent insulin release
Glucose enters the beta cells
through the glucose transporter GLUT2
Glucose goes into the
glycolysis and the respiratory cycle where multiple high-energy ATP molecules
are produced by oxidation
Dependent on blood glucose levels
and hence ATP levels, the ATP controlled potassium channels (K+) close and the
cell membranes depolarize
On depolarisation, voltage
controlled calcium channels (Ca2+) open and calcium flows into the cells
An increased calcium level
causes activation of phospholipase C, which cleaves the membrane phospholipid
phosphatidyl inositol 4,5-bisphosphate into inositol 1,4,5-triphosphate and
diacylglycerol.
Inositol 1,4,5-triphosphate (IP3)
binds to receptor proteins in the membrane of endoplasmic reticulum (ER). This
allows the release of Ca2+ from the ER via IP3 gated channels, and further
raises the cell concentration of calcium.
Significantly increased amounts of calcium in the
cells causes release of previously synthesised insulin, which has been stored
in secretory vesicles
This is the main mechanism for
release of insulin and regulation of insulin synthesis. In addition some
insulin synthesis and release takes place generally at food intake, not just
glucose or carbohydrate intake, and the beta cells are also somewhat influenced
by the autonomic nervous system. The signalling mechanisms controlling this are
not fully understood.
Other substances known which
stimulate insulin release are acetylcholine, released from vagus nerve endings
(parasympathetic nervous system), cholecystokinin, released by enteroendocrine
cells of intestinal mucosa and glucose-dependent insulinotropic peptide (GIP).
The first of these act similarly as glucose through phospholipase C, while the
last acts through the mechanism of adenylate cyclase.
The sympathetic nervous system
(via α2-adrenergic agonists such as
norepinephrine) inhibits the release of insulin.
When the glucose level comes
down to the usual physiologic value, insulin release from the beta cells slows
or stops. If blood glucose levels drop lower than this, especially to
dangerously low levels, release of hyperglycemic hormones (most prominently
glucagon from Islet of Langerhans' alpha cells) forces release of glucose into
the blood from cellular stores, primarily liver cell stores of glycogen. By
increasing blood glucose, the hyperglycemic hormones correct life-threatening
hypoglycemia. Release of insulin is strongly inhibited by the stress hormone
norepinephrine (noradrenaline), which leads to increased blood glucose levels
during stress.
Signal transduction
There are special transporter
proteins in cell membranes
through which glucose from the
blood can enter a cell. These transporters are, indirectly, under insulin
control in certain body cell types (eg, muscle cells). Low levels of
circulating insulin, or its absence, will prevent glucose from entering those
cells (eg, in untreated Type 1 diabetes). However, more commonly there is a
decrease in the sensitivity of cells to insulin (eg, the reduced insulin sensitivity
characteristic of Type 2 diabetes), resulting in decreased glucose absorption.
In either case, there is 'cell starvation', weight loss, sometimes extreme. In
a few cases, there is a defect in the release of insulin from the pancreas.
Either way, the effect is, characteristically, the same: elevated blood glucose
levels.
Activation of insulin
receptors leads to internal cellular mechanisms which directly affect glucose
uptake by regulating the number and operation of protein molecules in the cell
membrane which transport glucose into the cell. The genes which specify the
proteins which make up the insulin receptor in cell membranes have been
identified and the structure of the interior, cell membrane section, and now,
finally after more than a decade, the extra-membrane structure of receptor
(Australian researchers announced the work 2Q 2006).
Two types of tissues are most
strongly influenced by insulin, as far as the stimulation of glucose uptake is
concerned: muscle cells (myocytes) and fat
cells (adipocytes). The former are important because of their central
role in movement,
Together, they account for about two-thirds of all
cells in a typical human body.
Hypoglycemia
Although other cells can use other fuels for a while
growth hormone
(most prominently fatty acids), neuron
breathing, circulation, etc,
and the latter because they accumulate excess food energy against future ..
s
depend on glucose as a source of energy in the
non-starving human. They do not require insulin to absorb glucose, unlike
muscle and adipose tissue, and they have very small internal stores of
glycogen. Glycogen stored in liver cells (unlike glycogen stored in muscle
cells) can be converted to glucose, and released into the blood, when glucose
from digestion is low or absent, and the glycerol backbone in triglycerides can
also be used to produce blood glucose.
Exhaustion of these sources can, either temporarily or
on a sustained basis, if reducing blood glucose to a sufficiently low level,
first and most dramatically manifest itself in impaired functioning of the
central nervous system – dizziness, speech problems, even loss of
consciousness, are not unknown. This is known as hypoglycemia or, in cases
producing unconsciousness, "hypoglycemic coma" (formerly termed
"insulin shock" from the most common causative agent). Endogenous
causes of insulin excess (such as an insulinoma) 
are very rare, and the overwhelming majority of
hypoglycemia cases are caused by human action (e.g., iatrogenic, caused by
medicine) and are usually accidental. There have been a few reported cases of
murder, attempted murder, or suicide using insulin overdoses, but most insulin
shocks appear to be due to mismanagement of insulin (didn't eat as much as
anticipated, or exercised more than expected), or a mistake (e.g., 20 units of
insulin instead of 2).
Possible causes of hypoglycemia include:
Diabetic Nephropathy
(kidney diseases) Diabetic Neuropathy
(nervous systems diseases)
Diabetic
Retinopathy (eye diseases) Hypoglycemia (low
blood sugar)
Oral hypoglycemic agents (e.g., any of the
sulfonylureas, or similar drugs, which increase insulin release from beta cells
in response to a particular blood glucose level).
External insulin (usually injected subcutaneously).
Ingestion of low-carbohydrate sugar substitutes
(animal studies show these can trigger insulin release (albeit in much smaller
quantities than sugar) according to a report in Discover magazine, August 2005,
p18).
Diabetes
mellitus – general term referring to all
states characterized by hyperglycemia.
http://www.youtube.com/watch?v=VLiTbb6MaEU&NR=1
For the disease characterized
by excretion of large amounts of very dilute urine, see diabetes insipidus. For
diabetes mellitus in pets, see diabetes in cats and dogs.
Diabetes mellitus (IPA
pronunciation: is a metabolic disorder characterized by hyperglycemia (high
blood sugar) and other signs, as distinct from a single illness or condition.
The World Health Organization
recognizes three main forms of diabetes: type 1, type 2, and gestational
diabetes (occurring during pregnancy),[ which have similar signs, symptoms,
and consequences, but different causes and population distributions.
Ultimately, all forms are due to the beta cells of the pancreas being unable to
produce sufficient insulin to prevent hyperglycemia Type 1 is usually due to
autoimmune destruction of the pancreatic beta cells which produce insulin. Type
2 is characterized by tissue-wide insulin resistance and varies widely; it
sometimes progresses to loss of beta cell function. Gestational diabetes is
similar to type 2 diabetes, in that it involves insulin resistance; the
hormones of pregnancy cause insulin resistance in those women genetically
predisposed to developing this condition.
Types 1 and 2 are incurable chronic
conditions, but have been treatable since insulin became medically available in
1921, and are nowadays usually managed with a combination of dietary treatment,
tablets (in type 2) and, frequently, insulin supplementation. Gestational
diabetes typically resolves with delivery.
Diabetes
can cause many complications. Acute complications (hypoglycemia, ketoacidosis
or nonketotic hyperosmolar coma) may occur if the disease is not adequately
controlled. Serious long-term complications include cardiovascular disease
(doubled risk), chronic renal failure (diabetic nephropathy is the main cause
of dialysis in developed world adults), retinal damage (which can lead to
blindness and is the most significant cause of adult blindness in the
non-elderly in the developed world), nerve damage (of several kinds), and
microvascular damage, which may cause erectile dysfunction (impotence) and poor
healing. Poor healing of wounds, particularly of the feet, can lead to gangrene
which can require amputation — the leading cause of non-traumatic amputation in
adults in the developed world. Adequate treatment of diabetes, as well as
increased emphasis on blood pressure control and lifestyle factors (such as
smoking and keeping a healthy body weight), may improve the risk profile of most aforementioned complications.
Diabetes mellitus
Terminology
The term diabetes (Greek:
διαβήτης) was coined by Aretaeus of
Cappadocia. It is derived from the Greek word διαβαίνειν,
diabaínein that literally means "passing through," or
"siphon", a reference to one of diabetes' major symptoms—excessive
urine production. In 1675 Thomas Willis added the word mellitus to the disease,
a word from Latin meaning "honey", a reference to the sweet taste of
the urine. This sweet taste had been noticed in urine by the ancient Greeks,
Chinese, Egyptians, and Indians. In 1776 Matthew Dobson confirmed that the
sweet taste was because of an excess of a kind of sugar in the urine and blood
of people with diabetes.[3]
The ancient Indians tested for
diabetes by observing whether ants were attracted to a person's urine, and
called the ailment "sweet urine disease" (Madhumeha). The Korean,
Chinese, and Japanese words for diabetes are based on the same ideographs which
mean "sugar urine disease".
Diabetes, without
qualification, usually refers to diabetes mellitus, but there are several rarer
conditions also named diabetes. The most common of these is diabetes insipidus
(insipidus meaning "without taste" in Latin) in which the urine is
not sweet; it can be caused by either kidney (nephrogenic DI) or pituitary
gland (central DI) damage.
The term "type 1 diabetes"
has universally replaced several former terms, including childhood-onset
diabetes, juvenile diabetes, and insulin-dependent diabetes. "Type 2
diabetes" has also replaced several older terms, including adult-onset
diabetes, obesity-related diabetes, and non-insulin-dependent diabetes. Beyond
these numbers, there is no agreed standard. Various sources have defined
"type 3 diabetes" as, among others:
http://www.youtube.com/watch?v=V1LjRi8Nvv4
Gestational
diabetes
Insulin-resistant type 1 diabetes
(or "double diabetes")
Type 2 diabetes which has
progressed to require injected insulin.
Latent autoimmune diabetes of
adults (or LADA or "type 1.5" diabetes)
The distinction between what
is now known as type 1 diabetes and type 2 diabetes was first clearly made by
Sir Harold Percival (Harry) Himsworth, and published in January 1936.
Other landmark discoveries include: identification
of the first of the sulfonylureas in 1942 the determination of the amino acid
order of insulin (by Sir Frederick Sanger, for which he received a Nobel Prize)
the radioimmunoassay for insulin, as discovered by
identification of the first thiazolidinedione as an
effective insulin sensitizer during the 1990s .
Type 1 diabetes mellitus
Type 1 diabetes
mellitus—formerly known as insulin-dependent diabetes (IDDM), childhood
diabetes or also known as juvenile diabetes, is characterized by loss of the
insulin-producing beta cells of the islets of Langerhans of the pancreas
leading to a deficiency of insulin. It should be noted that there is no known preventative
measure that can be taken against type 1 diabetes. Most people affected by type
1 diabetes are otherwise healthy and of a healthy weight when onset occurs.
Diet and exercise cannot reverse or prevent type 1 diabetes. Sensitivity and
responsiveness to insulin are usually normal, especially in the early stages.
This type comprises up to 10% of total cases in North America and Europe,
though this varies by geographical location. This type of diabetes can affect
children or adults but was traditionally termed "juvenile diabetes"
because it represents a majority of cases of diabetes affecting children.
The main
cause of beta cell loss leading to type 1 diabetes is a T-cell mediated
autoimmune attack. The principal treatment of type 1 diabetes, even from the
earliest stages, is replacement of insulin. Without insulin, ketosis and
diabetic ketoacidosis can develop and coma or death will result.
Currently,
type 1 diabetes can be treated only with insulin, with careful monitoring of
blood glucose levels using blood testing monitors. Emphasis is also placed on
lifestyle adjustments (diet and exercise). Apart from the common subcutaneous
injections, it is also possible to deliver insulin by a pump, which allows
continuous infusion of insulin 24 hours a day at preset levels and the ability
to program doses (a bolus) of insulin as needed at meal times. An inhaled form
of insulin, Exubera, was approved by the FDA in January 2006.
Type 1
treatment must be continued indefinitely. Treatment does not impair normal activities,
if sufficient awareness, appropriate care, and discipline in testing and
medication is taken. The average glucose level for the type 1 patient should be
as close to normal (80–120 mg/dl, 4–6 mmol/l) as possible. Some physicians
suggest up to 140–150 mg/dl (7-7.5 mmol/l) for those having trouble with lower
values, such as frequent hypoglycemic events. Values above 200 mg/dl (10
mmol/l) are often accompanied by discomfort and
frequent urination leading to dehydration. Values above 300 mg/dl (15 mmol/l)
usually require immediate treatment and may lead to ketoacidosis. Low levels of
blood glucose, called hypoglycemia, may lead to seizures or episodes of
unconsciousness.
Type 2
diabetes mellitus
Main article:
Diabetes mellitus type 2
http://www.youtube.com/watch?v=ZsTSoLhl3Y4&feature=related
http://www.youtube.com/watch?v=nBJN7DH83HA&feature=related
Type 2
diabetes mellitus—previously known as adult-onset diabetes, maturity-onset
diabetes, or non-insulin-dependent diabetes mellitus (NIDDM)—is due to a
combination of defective insulin secretion and insulin resistance or reduced
insulin sensitivity (defective responsiveness of tissues to insulin), which
almost certainly involves the insulin receptor in cell membranes. In the early
stage the predominant abnormality is reduced insulin sensitivity, characterized
by elevated levels of insulin in the blood. At this stage hyperglycemia can be
reversed by a variety of measures and medications that improve insulin
sensitivity or reduce glucose production by the liver, but as the disease
progresses the impairment of insulin secretion worsens, and therapeutic
replacement of insulin often becomes necessary. There are numerous theories as
to the exact cause and mechanism for this resistance, but central obesity (fat
concentrated around the waist in relation to abdominal organs, and not
subcutaneous fat, it seems) is known to predispose individuals for insulin
resistance, possibly due to its secretion of adipokines (a group of hormones)
that impair glucose tolerance. Abdominal fat is especially active hormonally.
Obesity is found in approximately 55% of patients diagnosed with type 2
diabetes.[13] Other factors include aging (about 20% of elderly patients are
diabetic in North America) and family history (Type 2 is much more common in
those with close relatives who have had it), although in the last decade it has
increasingly begun to affect children and adolescents, likely in connection
with the greatly increased childhood obesity seen in recent decades in some
places.
Type 2
diabetes may go unnoticed for years in a patient before diagnosis, as visible
symptoms are typically mild or non-existent, without ketoacidotic episodes, and
can be sporadic as well. However, severe long-term complications can result
from unnoticed type 2 diabetes, including renal failure, vascular disease
(including coronary artery disease), vision damage, etc.
Fetal/neonatal risks associated with
GDM include congenital anomalies such as cardiac, central nervous system, and
skeletal muscle malformations. Increased fetal insulin may inhibit fetal
surfactant production and cause respiratory distress syndrome.
Hyperbilirubinemia may result from red blood cell destruction. In severe cases,
perinatal death may occur, most commonly as a result of poor placental
profusion due to vascular impairment. Induction may be indicated with decreased
placental function. Cesarean section may be performed if there is marked fetal
distress or an increased risk of injury associated with macrosomia, such as
shoulder dystocia.
Genetics
Both type 1 and type 2
diabetes are at least partly inherited. Type 1 diabetes appears to be triggered
by some (mainly viral) infections, or in a less common group, by stress or
environmental exposure (such as exposure to certain chemicals or drugs). There
is a genetic element in individual susceptibility to some of these triggers which
has been traced to particular HLA genotypes (i.e., the genetic "self"
identifiers relied upon by the immune system). However, even in those who have
inherited the susceptibility, type 1 diabetes mellitus seems to require an
environmental trigger. A small proportion of people with type 1 diabetes carry
a mutated gene that causes maturity onset diabetes of the young (MODY).
When the glucose concentration in the
blood is high (ie, above the "renal threshold"), reabsorption of
glucose in the proximal renal tubuli is incomplete, and part of the glucose
remains in the urine (glycosuria). This increases the osmotic pressure of the
urine and thus inhibits the resorption of water by the kidney, resulting in an
increased urine producton (polyuria) and an increased fluid loss. Lost blood
volume will be replaced osmotically from water held in body cells, causing
dehydration and increased thirst.
Prolonged high blood glucose
causes glucose absorption and so shape changes in the shape of the lens in the
eye, leading to vision changes. Blurred vision is a common complaint leading to
a diabetes diagnosis; Type 1 should always be suspected in cases of rapid
vision change. Type 2 is generally more gradual, but should still be suspected.
A rarer, but equally severe, possibility
is hyperosmolar nonketotic state, which is more common in type 2 diabetes, and
is mainly the result of dehydration due to loss of body water. Often, the
patient has been drinking extreme amounts of sugar-containing drinks, leading
to a vicious circle in regard to the water loss.
Diagnostic approach
The diagnosis of type 1 diabetes, and many cases of
type 2, is usually prompted by recent-onset symptoms of excessive urination
(polyuria) and excessive thirst (polydipsia), often accompanied by weight loss.
These symptoms typically worsen over days to weeks; about 25% of people with
new type 1 diabetes have developed some degree of diabetic ketoacidosis by the
time the diabetes is recognized. The diagnosis of other types of diabetes is
usually made in other ways. The most common are ordinary health screening,
detection of hyperglycemia when a doctor is investigating a complication of
longstanding, though unrecognized, diabetes, and new signs and symptoms due to the diabetes,
such as vision changes or unexplainable fatigue.
Diabetes screening is recommended for
many people at various stages of life, and for those with any of several risk
factors. The screening test varies according to circumstances and local policy,
and may be a random blood glucose test, a fasting blood glucose test, a blood
glucose test two hours after
Complications
The complications of diabetes
are far less common and less severe in people who have well-controlled blood
sugar levels. In fact, the better the control, the lower the risk of
complications.
Hence patient education,
understanding, and participation is vital. Healthcare professionals treating
diabetes also often attempt to address health issues that may accelerate the
deleterious effects of diabetes. These include smoking (stopping), elevated
cholesterol levels (control or reduction with diet, exercise or medication),
obesity (even modest weight loss can be beneficial), high blood pressure
(exercise or medication if needed), and lack of regular exercise.
Blood Test
To monitor the amount of
glucose within the blood a person with diabetes should test their blood
regularly. The procedure is quite simple and can often be done at home.
Acute complications
Main articles: Diabetic
ketoacidosis , Nonketotic hyperosmolar coma , Hypoglycemia and Diabetic coma
Diabetic ketoacidosis
Diabetic ketoacidosis (DKA) is
an acute, dangerous complication and is always a medical emergency. On
presentation at hospital, the patient in DKA is typically dehydrated and
breathing both fast and deeply. Abdominal pain is common and may be severe. The
level of consciousness is typically normal until late in the process, when
lethargy (dulled or reduced level of alertness or consciousness) may progress
to coma. Ketoacidosis can become severe enough to cause hypotension, shock, and
death. Prompt proper treatment usually results in full recovery, though death
can result from inadequate treatment, delayed treatment or from a variety of
complications. It is much more common in type 1 diabetes than type 2, but can
still occur in patients with type 2 diabetes.
Nonketotic hyperosmolar coma
While not generally
progressing to coma, this hyperosmolar nonketotic state (HNS) is another acute
problem associated with diabetes mellitus. It has many symptoms in common with
DKA, but an entirely different cause, and requires different treatment. In
anyone with very high blood glucose levels (usually considered to be above 300
mg/dl (16 mmol/l)), water will be osmotically drawn out of cells into the
blood. The kidneys will also be "dumping" glucose into the urine,
resulting in concomitant loss of water, and causing an increase in blood
osmolality. If fluid is not replaced (by mouth or intravenously), the osmotic
effect of high glucose levels combined with the loss of water will eventually
result in very high serum osmolality (ie, dehydration). The body's cells will
become progressively dehydrated as water is taken from them and excreted.
Electrolyte imbalances are also common, and dangerous. This combination of
changes, especially if prolonged, will result in symptoms of lethargy (dulled
or reduced level of alertness or consciousness) and may progress to coma. As
with DKA urgent medical treatment is necessary, especially volume replacement.
This is the 'diabetic coma' which more commonly occurs in type 2 diabetics.
Etiology, pathogenesis and
genetics of diabetes mellitus.
Proinsulin consists of three domains:
an amino-terminal B chain, a carboxy-terminal A chain and a connecting peptide
in the middle known as the C peptide.
Within the endoplasmic reticulum, proinsulin
is exposed to several specific endopeptidases which excise the C peptide,
thereby generating the mature form of insulin. Insulin and free C peptide are
packaged in the Golgi into secretory granules which accumulate in the
cytoplasm.
Control of Insulin Secretion
Insulin is secreted in
primarily in response to elevated blood concentrations of glucose. This makes
sense because insulin is "in charge" of facilitating glucose entry into
cells. Some neural stimuli (e.g. sight and taste of food) and increased blood
concentrations of other fuel molecules, including amino acids and fatty acids,
also promote insulin secretion.
http://www.youtube.com/watch?v=Gmm7DjG-rDs&feature=related
Our understanding of the
mechanisms behind insulin secretion remain somewhat fragmentary. Nonetheless,
certain features of this process have been clearly and repeatedly demonstrated,
yielding the following model:
Glucose is transported into the B cell by
facilitated diffusion through a glucose transporter; elevated concentrations of
glucose in extracellular fluid lead to elevated concentrations of glucose
within the B cell.
Glucose Test
A person with diabetes constantly manages their
blood's sugar (glucose) levels. After a blood sample is taken and tested, it is
determined whether the glucose levels are low or high. If glucose levels are
too low carbohydrates are ingested.If glucose in the blood is too high, the
appropriate amount of insulin is administered into the body such as through an
insulin pump.
http://www.youtube.com/watch?v=cTDWZp4sLuU&feature=related
Elevated concentrations of glucose within the
B cell ultimately leads to membrane depolarization and an influx of
extracellular calcium. The resulting increase in intracellular calcium is
thought to be one of the primary triggers for exocytosis of insulin-containing
secretory granules. The mechanisms by which elevated glucose levels within the
B cell cause depolarization is not clearly established, but seems to result
from metabolism of glucose and other fuel molecules within the cell, perhaps sensed
as an alteration of ATP:ADP ratio and transduced into alterations in membrane
conductance.
Stimulation of insulin release is
readily observed in whole animals or people. The normal fasting blood glucose
concentration in humans and most mammals is 80 to 90 mg per 100 ml, associated
with very low levels of insulin secretion.
Immediately after the increasing the
level of glycemia begins, plasma insulin levels increase dramatically. This initial
increase is due to secretion of preformed insulin, which is soon significantly
depleted. The secondary rise in insulin reflects the considerable amount of
newly synthesized insulin that is released immediately. Clearly, elevated
glucose not only simulates insulin secretion, but also transcription of the
insulin gene and translation of its mRNA.
Physiologic
effects opf insulin
Stand on a streetcorner and
ask people if they know what insulin is, and many will reply, "Doesn't it
have something to do with blood sugar?" Indeed, that is correct, but such
a response is a bit like saying "Mozart? Wasn't he some kind of a
musician?"
Insulin is a key player in the
control of intermediary metabolism. It has profound effects on both
carbohydrate and lipid metabolism, and significant influences on protein and
mineral metabolism. Consequently, derangements in insulin signalling have
widespread and devastating effects on many organs and tissues.
The Insulin
Receptor
Like the receptors for other
protein hormones, the receptor for insulin is embedded in the plasma membrane.
The insulin receptor is composed of two alpha subunits and two beta subunits
linked by disulfide bonds. The alpha chains are entirely extracellular and
house insulin binding domains, while the linked beta chains penetrate through
the plasma membrane.
The insulin receptor is a tyrosine
kinase. In other words, it functions as an enzyme that transfers phosphate
groups from ATP to tyrosine residues on intracellular target proteins. Binding
of insulin to the alpha subunits causes the beta subunits to phosphorylate
themselves (autophosphorylation), thus activating the catalytic activity of the
receptor. The activated receptor then phosphorylates a number of intracellular
proteins, which in turn alters their activity, thereby generating a biological
response.
Several intracellular proteins
have been identified as phosphorylation substrates for the insulin receptor,
the best-studied of which is insulin receptor substrate 1 or IRS-1. When IRS-1
is activated by phosphorylation, a lot of things happen. Among other things,
IRS-1 serves as a type of docking center for recruitment and activation of
other enzymes that ultimately mediate insulin's effects.
The action of insuin
Insulin is an anabolic hormone
(promotes the synthesis of carbohydrates, proteins, lipids and nucleic acids).
The most important target
organs for insulin action are:
- liver
-
muscles 
-
adipocytes.
The brain and blood cells are unresponsive to insulin.
Insulin and Carbohydrate Metabolism
Glucose is liberated from dietary
carbohydrate such as starch or sucrose by hydrolysis within the small
intestine, and is then absorbed into the blood. Elevated concentrations of
glucose in blood stimulate release of insulin, and insulin acts on cells
thoughout the body to stimulate uptake, utilization and storage of glucose. The
effects of insulin on glucose metabolism vary depending on the target tissue.
The effects of insulin on
carbohydrate metabolism include:
1. Insulin facilitates entry
of glucose into muscle, adipose and several other tissues.
The only mechanism by which
cells can take up glucose is by facilitated diffusion through a family of
hexose transporters. In many tissues - muscle being a prime example - the major
transporter used for uptake of glucose (called GLUT4) is made available in the
plasma membrane through the action of insulin.
In the absense of insulin, GLUT4
glucose transporters are present in cytoplasmic vesicles, where they are
useless for transporting glucose. Binding of insulin to receptors on such cells
leads rapidly to fusion of those vesicles with the plasma membrane and
insertion of the glucose transporters, thereby giving the cell an ability to
efficiently take up glucose. When blood levels of insulin decrease and insulin
receptors are no longer occupied, the glucose transporters are recycled back
into the cytoplasm.
It should be noted here that
there are some tissues that do not require insulin for efficient uptake of
glucose: important examples are brain and the liver. This is because these
cells don't use GLUT4 for importing glucose, but rather, another transporter
that is not insulin-dependent.
2. Insulin stimulates the
liver to store glucose in the form of glycogen .
A large fraction of glucose absorbed
from the small intestine is immediately taken up by hepatocytes, which convert
it into the storage polymer glycogen.
Insulin has several effects in
liver which stimulate glycogen synthesis. First, it activates the enzyme
hexokinase, which phosphorylates glucose, trapping it within the cell.
Coincidently, insulin acts to inhibit the activity of glucose-6-phosphatase.
Insulin also activates several of the enzymes that are directly involved in
glycogen synthesis, including phosphofructokinase and glycogen synthase. The
net effect is clear: when the supply of glucose is abundant, insulin
"tells" the liver to bank as much of it as possible for use later.
3. Insulin inhibits glucose formation
– from glycogen (glycogenolysis) and – from amino-acid precursors
(glyconeogenesis).
As aresult - well-known effect
of insulin is to decrease the concentration of glucose in blood, which should
make sense considering the mechanisms described above. Another important consideration
is that, as blood glucose concentrations fall, insulin secretion ceases. In the
absense of insulin, a bulk of the cells in the body become unable to take up
glucose, and begin a switch to using alternative fuels like fatty acids for
energy. Neurons, however, require a constant supply of glucose, which in the
short term, is provided from glycogen reserves.
In the absense of insulin, glycogen
synthesis in the liver ceases and enzymes responsible for breakdown of glycogen
become active. Glycogen breakdown is stimulated not only by the absense of
insulin but by the presence of glucagon, which is secreted when blood glucose
levels fall below the normal range.
Insulin and Protein
Metabolism:
1. Insulin transfers of amino
acids across plasma membranes.
2. Insulin stimulates of
protein synthesis.
3. Insulin inhibites of
proteolysis.
Insulin and Lipid Metabolism
The metabolic pathways for
utilization of fats and carbohydrates are deeply and intricately intertwined.
Considering insulin's profound effects on carbohydrate metabolism, it stands to
reason that insulin also has important effects on lipid metabolism. Important
effects of insulin on lipid metabolism include the following:
1. Insulin promotes synthesis of fatty acids in the
liver. As discussed above, insulin is stimulatory to synthesis of glycogen in
the liver. However, as glycogen accumulates to high levels (roughly 5% of liver
mass), further synthesis is strongly suppressed.
When the liver is saturated with
glycogen, any additional glucose taken up by hepatocytes is shunted into
pathways leading to synthesis of fatty acids, which are exported from the liver
as lipoproteins. The lipoproteins are ripped apart in the circulation,
providing free fatty acids for use in other tissues, including adipocytes,
which use them to synthesize triglyceride.
2. Insulin inhibits breakdown of fat in adipose tissue
(lipolisis) by inhibiting theintracellular lipase that hydrolyzes triglycerides
to release fatty acids.
Insulin facilitates entry of glucose into adipocytes,
and within those cells, glucose can be used to synthesize glycerol. This
glycerol, along with the fatty acids delivered from the liver, are used to
synthesize triglyceride within the adipocyte. By these mechanisms, insulin is
involved in further accumulation of triglyceride in fat cells.
From a whole body perspective, insulin has a
fat-sparing effect. Not only does it drive most cells to preferentially oxidize
carbohydrates instead of fatty acids for energy, insulin indirectly stimulates
accumulation of fat is adipose tissue.
Other effects:
1. Insulin stimulates the intracellular flew of
potassium, phosphate and magnesium in the heart.
2. Insulin inhibits inotropic and chronoropic action
(unrelated to hypoglycemia).
The action of insulin can be decreased by:
-
glucagons: stimulates glycogenolysis and glyconeogenesis;
-
somatostatin: inhibits secretion of insulin and regulates glucose
absorption from alimentary tract into blood;
-
glucocorticoids: decrease of glucose utilization by tissues, stimulate
glycogenolysis and glyconeogenesis, increase lipogenesis (in patients with
insulinorsistancy);
-
katecholamines (adrenaline): inhibits β-cells secretion, stimulates
glycogenolysis and ACTH secretion;
-
somatotropin: stimulates α-cells (which secret glucagon), increases
activity of enzymes which destroy the insulin, stimulates glyconeogenesis,
increases of glucose exit from the liver veins into blood, decreases of glucose
utilization by tissues;
- ACTH:
stimulates glucocorticoides secretion and β-cells secretion;
-
thyroid hormones: increase glucose absorption into blood, stimulate
glycogenolysis, inhibit fat formation from the carbohydrates.
Absolute insulin insufficiency means that pancreas
produce insulin in very low quantities or doesn’t produce it at all (due to
destruction of beta-cells by inflammative, autoimmune process or surgery).
Relative insulin insufficiency means that pancreas
produces or can produce insulin but it doesn’t “work”. (The pathologic process
can be on the next levels:
- beta
cells: they can be not sensitive for the high level of glycemia;
-
insulin: abnormal insulin, insulin antibodies, contrainsulin hormones,
absence of enzyme, which activates proinsulin (into insulin));
-
receptors (decreased receptor number or diminished binding of insulin).
Type 1, or insulin-dependent diabetes mellitus is
characterized by pancreatic islet beta cell destruction and absolute insulinopenia.
Type I Diabetes
In response to high levels of glucose in the blood,
the insulin-producing cells in the pancreas secrete the hormone insulin. Type I
diabetes occurs when these cells are destroyed by the body's own imune system.
This individuals are ketosis prone
under basal conditions. The onset of the disease is generally in youth, but it
can occur at any age. Patients have dependence on daily insulin administration
for survival.
Current formulation of the
pathogenesis of type 1 DM includes the following:
1. A genetic predisposition, conferred by
diabetogenic genes on the short arm of chromosome C, either as part of it or in
close proximity to the major histocompatibility complex (MMHC) region (more
than 95 % of type 1 diabetes individuals are HLA DR3, DR4 or DR3/DR4; on the
other hand, HLA DR2 confers protection against the development of type 1 DM);
2. Putative
environmental triggers (possibly viral infections (Coxsackie B, rubella, mumps)
or chemical toxins (nitrosourea compounds)) that in genetically susceptible
individuals might play a role in initiating the disease process.
3. An immune
mechanism gone awry, either initiation of immune destruction or loss of
tolerance, leading to slow, progressive loss of pancreatic islet beta cells and
eventual clinical onset of type 1 diabetes.
Stages of type 1 DM development (by Flier, 1986)
I.
A genetic predisposition or changes of immunity.
Normal β-cells
II.
Putative environmental triggers.
III.
Active autoimmune insulities with
β-cells destruction.
Insulinitis
IV.
Progression of autoimmune insulities with destruction of >50 % of
β-cells.
V.
Development of manifest DM.
VI. Total β-cells destruction.
I.
A genetic predisposition or changes
of immunity.
Normal β-cells
II.
Putative environmental triggers.
III.
Active autoimmune insulities with β-cells destruction.
Insulinitis
IV.
Progression of autoimmune insulities
with destruction of >50 % of β-cells.
V.
Development of manifest DM.
VI.
Total β-cells destruction.
β-cells destruction
Type 2 or non-insulin-dependent
diabetes mellitus is the most common form of diabetes, accounting for 95 – 90 %
of the diabetic population. (Video) Most investigators agree that genetic
factors underlie NIDDM, but it is probably not caused by defects at a single
gene locus. Obesity, diet, physical activity, intrauterine environment, and
stress are among the most commonly implicated environmental factors which play
a role in the development of the disease. In patients with type 2 DM mostly we
can find relative insulin insufficiency (when pancreatic gland secrets insulin
but it can have changed structure or weight, or circulating enzymes and
antibodies destroy normal insulin, or there are changes of insulin receptors).
Pathogenetic
and clinical difference of type 1 and type 2 DM.
I. Type 1
of DM (destruction of β-cells which
mostly leads to absolute insulin insufficiency):
-
autoimmune;
-
idiopathic.
II. Type 2 of
DM (resistance to insulin and relative insulin insufficiency or defect of
insulin secretion with or without resistance to insulin).
III.
Other specific types:
-
genetic defects of β-cells function;
- genetic
defects of insulin action;
-
pancreatic diseases (chronic
pancreatitis; trauma, pancreatectomy; tumor of pancreatic gland;
fibrocalculosis; hemochromatosis);
-
endocrine disease;
- drug
exposures;
-
infections and others.
Skin
Diabetes can affect every part of the body, including
the skin. The skin is a common target of DM As many as one third of people with
diabetes will have a skin disorder caused or affected by diabetes at some time
in their lives. In fact, such problems are sometimes the first sign that a
person has diabetes. Luckily, most skin conditions can be prevented or easily
treated if caught early.
Some of these problems are
skin conditions anyone can have, but people with diabetes get more easily. These
include bacterial infections, fungal infections, and itching. Other skin
problems happen mostly or only to people with diabetes. These include diabetic
dermopathy, necrobiosis lipoidica diabeticorum, diabetic blisters, and eruptive
xanthomatosis.
Bacterial Infections
Several kinds of bacterial
infections occur in people with diabetes. One common one are styes. These are
infections of the glands of the eyelid. Another kind of infection are boils, or
infections of the hair follicles. Carbuncles are deep infections of the skin
and the tissue underneath. Infections can also occur around the nails.
Inflamed tissues are usually
hot, swollen, red, and painful. Several different organisms can cause
infections. The most common ones are the Staphylococcus bacteria, also called
staph.
Once, bacterial infections were life
threatening, especially for people with diabetes. Today, death is rare, thanks
to antibiotics and better methods of blood sugar control.
But even today, people with diabetes have more
bacterial infections than other people do.
Fungal Infections
The culprit in fungal
infections of people with diabetes is often Candida albicans. This yeast-like
fungus can create itchy rashes of moist, red areas surrounded by tiny blisters
and scales. These infections often occur in warm, moist folds of the skin.
Problem areas are under the breasts, around the nails, between fingers and
toes, in the corners of the mouth, under the foreskin (in uncircumcised men),
and in the armpits and groin.
Common fungal infections
include jock itch, athlete's foot, ringworm (a ring-shaped itchy patch), and
vaginal infection that causes itching.
Itching
Localized itching is often caused by
diabetes. It can be caused by a yeast infection, dry skin, or poor circulation.
When poor circulation is the cause of itching, the itchiest areas may be the
lower parts of the legs.
Diabetic Dermopathy
Diabetes can cause changes in
the small blood vessels. These changes can cause skin problems called diabetic
dermopathy.
Dermopathy often looks like
light brown, scaly patches. These patches may be oval or circular. Some people
mistake them for age spots. This disorder most often occurs on the front of
both legs. But the legs may not be affected to the same degree. The patches do
not hurt, open up, or itch.
Necrobiosis Lipoidica Diabeticorum
Another disease that may be
caused by changes in the blood vessels is necrobiosis lipoidica diabeticorum
(NLD). NLD is similar to diabetic dermopathy. The difference is that the spots
are fewer, but larger and deeper.Iit consists of skin necrosis with lipid
infiltration and is also characteristically found in the pretibial area. The
lesions resemble red plaques with distinct border.s
NLD often starts as a dull red
raised area. After a while, it looks like a shiny scar with a violet border.
The blood vessels under the skin may become easier to see. Sometimes NLD is
itchy and painful. Sometimes the spots crack open.
NLD is a rare condition. Adult
women are the most likely to get it. As long as the sores do not break open,
you do not need to have it treated. But if you get open sores, see your doctor
for treatment.
Atherosclerosis
Thickening of the arteries - atherosclerosis - can
affect the skin on the legs. People with diabetes tend to get atherosclerosis
at younger ages than other people do.
As atherosclerosis narrows the blood vessels, the skin
changes. It becomes hairless, thin,
cool, and shiny. The toes become cold. Toenails thicken and discolor. And
exercise causes pain in the calf muscles because the muscles are not getting
enough oxygen.
Because blood carries the
infection-fighting white cells, affected legs heal slowly when the skin in
injured. Even minor scrapes can result in open sores that heal slowly.
People with neuropathy are
more likely to suffer foot injuries. These occur because the person does not
feel pain, heat, cold, or pressure as well. The person can have an injured foot
and not know about it. The wound goes uncared for, and so infections develop
easily. Atherosclerosis can make things worse. The reduced blood flow can cause
the infection to become severe.
Allergic Reactions
Allergic skin reactions can occur in
response to medicines, such as insulin or diabetes pills. You should see your
doctor if you think you are having a reaction to a medicine. Be on the lookout
for rashes, depressions, or bumps at the sites where you inject insulin.
Diabetic Blisters (Bullosis
Diabeticorum)
Rarely, people with diabetes
erupt in blisters. Diabetic blisters can occur on the backs of fingers, hands,
toes, feet, and sometimes, on legs or forearms.
These sores look like burn blisters. They sometimes
are large. But they are painless and have no redness around them. They heal by
themselves, usually without scars, in about three weeks. They often occur in
people who have diabetic neuropathy. The only treatment is to bring blood sugar
levels under control.
Eruptive Xanthomatosis
Eruptive xanthomas are usually
associated with very high serum triglycerides or chylimicrones. They may occur
in familial chylomicronaemia syndrome, lipoprotein lipase deficiency, severe
familial hypertriglyceridemia, excess alcohol intake, severe uncontrolled
diabetes. Treatment is to correct the underlying condition. Lowering
triglycerides will result in the clearance of the lesions.
Pict. This shown classic xanthelasma
around the eye. It may be associated with genetic hyperlipidaemias, although it
may occur with diabetes, biliary cirrhosis or without any associated
conditions.
Eruptive xanthomatosis is another
condition caused by diabetes that's out of control. It consists of firm,
yellow, pea-like enlargements in the skin. Each bump has a red halo and may
itch. This condition occurs most often on the backs of hands, feet, arms, legs,
elbows, knees and buttocks.
The disorder usually occurs in
young men with type 1 diabetes. The person often has high levels of cholesterol
and fat (particularly hyperchylomicronemia) in the blood. Like diabetic
blisters, these bumps disappear when diabetes control is restored.
Digital Sclerosis
Sometimes, people with
diabetes develop tight, thick, waxy skin on the backs of their hands. Sometimes
skin on the toes and forehead also becomes thick. The finger joints become
stiff and can no longer move the way they should. Rarely, knees, ankles, or
elbows also get stiff.
This condition happens to
about one third of people who have type 1 diabetes. The only treatment is to
bring blood sugar levels under control.
Disseminated Granuloma Annulare
In disseminated granuloma annulare,
the person has sharply defined ring-shaped or arc-shaped raised areas on the
skin. These rashes occur most often on parts of the body far from the trunk
(for example, the fingers or ears). But sometimes the raised areas occur on the
trunk. They can be red, red-brown, or skin-colored.
Subcutaneous adipose tissue
The abdomen type of obesity is common
in patients with type 2 DM. Sometimes generalized subcutaneous adipose tissue
atrophy can be observed in diabetics.
Bones and joints
Osteoporosis,
osteoarthropaphy, diabetic chairopathy (decreasing of the movements of joints)
can be find in patients with DM also.
Diabetic Blood Circulation in Foot
People with diabetes are at risk for blood vessel
injury, which may be severe enough to cause tissue damage in the legs and feet.
The heart, arteries,
arterioles, and capillaries can be affected. Cardiovascular changes tend to
occur earlier in patients with DM when compared with individuals of the same age.
Several factors play a role in the high incidence of coronary artery disease
seen in patients with DM. These include age of the patient, duration and
severity of the diabetes, and presence of other risk factors such as
hypertension, smoking and hyperlipoproteinemia. It has been suggested that in
some patients with DM, involvement of the small vessels of the heart can lead
to cardiomyopathy, independent of narrowing of the major coronary arteries.
Myocardial infarction is responsible for at least half of deaths in diabetic
patients, and mortality rate for the diabetics is higher than that for
nondiabetics of the same age who develop this complication.
Hypertension is common in
patients with DM, particularly in the presence of renal disease (as a result of
atherosclerosis, destruction of juxtaglomerular cells,
sympathetic-nervous-system dysfunction and volume expansion).
Atherosclerosis of femoral,
popliteal and calf larger arteries may lead to intermittent claudication, cold
extremities, numbness, tingling and gangrene.
Respiratory
system
Mucomycosis of the nasopharinx,
sinusitis, bronchitis, pneumonia, tuberculosis are more common in patients with
diabetes than in nondiabetics.
Kidneys and urinary tract
Renal disease include diabetic
nephropathy, necrosing renal papillitis, acute tubular necrosis, lupus
erythematosus, acute poststreptococcal and membranoproliferative
glomerulonephritis, focal glomerulosclerosis, idiopathic membranous
nephropathy, nonspecific immune complex glomerulonephritides, infections can
occur in any part of the urinary tract. Last are caused when bacteria, usually
from the digestive system, reach the urinary tract. If bacteria are growing in
the urethra, the infection is called urethritis. The bacteria may travel up the
urinary tract and cause a bladder infection, called cystitis. An untreated
infection may go farther into the body and cause pyelonephritis, a kidney
infection. Some people have chronic or recurrent urinary tract infections.
Eyes
Complications of
the eyes include: ceratities, retinatis, chorioretinatis, cataracts. The last
one occurs commonly in the patients with long-standing DM and may be related to
uncontrolled hyperglycemia (glucose metabolism by the lens does not require the
presence of insulin. The epithelial cells of the lens contain the enzyme aldose
reductase, which converts glucose into sorbitol. This sugar may be subsequently
converted into fructose by sorbitol dehydrogenase. Sorbitol is retained inside
the cells because of its difficulty in transversing plasma membranes. The rise
in intracellular osmolality leads to increased water uptake and swelling of the
lens).
Pict. Cataracta
The diagnosis of DM
The diagnosis of DM may be straightforward or very
difficult.
(The presence of the marked hyperglycemia, glucosuria,
polyuria, polydipsia, polyphagia, lethargy, a tendency to acquire infections,
and physical findings consistent with the disease should offer no difficulty in
arriving at the correct diagnosis. On the other hand, mild glucose intolerance
in the absence of symptoms or physical findings does not necessarily indicate
that DM is present.)
The diagnosis of DM include:
I. Clinical manifestations of DM.
II. Laboratory findings.
1) fasting
serum glucose (if the value is over 6,7 mmol/l (120 mg/dl) on two or more
separate days, the patient probably has DM);
2) the
glucose tolerance test (GTT):
If the diagnosis is still in doubt, then perform a
GTT.
The long-term degenerative changes in the blood, vessels,
the heart, the kidneys, the nervous system, and the eyes as responsible for the
most of the morbidity and mortality of DM. There is a causal relationship and
the level of the metabolic control.
Diabetic nephropathy.
It is usually asymptomatic
until end stage renal disease develops, but it can course the nephrotic
syndrome prior to the development of uremia. Nephropathy develops in 30 to 50 %
of type 1 DM patients and in small percentage of type 2 DM patients. Arteriolar
hyalinosis, a deposition of hyaline material in the lumen of the afferent and
efferent glomerular arterioles, is an almost pathognomic histologic lesion of
DM.
In the first few years of type
1 DM there is hyperfiltration which declines fairly steadily to return to a
normal value at approximately 10 years (blue line). After sbout 10 years there
is sustained proteinurea and by approximately 14 years it has reached nephritic
stage (red line). Renal function continues to decline, with the end stage being
reached at approximately 16 years
Atherosclerosis of large vessels
(macroangiopathy) leads to intermittent claudication, cold extremities and
other symptoms which can be also find while arteriols and capillaries are
affected (microangiopathy).
Ischemic heart disease.
1.
Cardiovascular changes tend to occur earlier in patients with DM when
compared with individuals of the same age.
2. Frequency
of myocardial infarction (MI) and mortality is higher in diabetics than that in
nondiabetis og the same age.
3. The
prognosis is even worse if ketoacidosis, or other complications of DM are
present.
4. Diabetic
patients have more complications of MI (arrhythmias, cardiogenic shock and
others) than nondiabetic ones.
5. Often can
observe atypical forms (without pain).
6. Male : female
= 1 : 1 (nondiabetics = 10 : 1).
Diabetic neuropathy.
It is an old clinical
observation that the symptoms of neuropathic dysfunction improve with better
control of DM, lending support to the idea that hyperglycemia plays an
important role. Accumulation of sorbitol and fructose in the diabetic nerves
leads to damage of the Schwann cells and segmental demyelination.
Classification of diabetic neuropathy.
I.
Encephalopathy (central neyropathy) is characterized by decreased
memory, headache, unadequate actions and others.
II.
Peripheral polyneuropathy (radiculoneuropathy). There are three types of
radiculoneuropathy:
-
distal polyradiculoneuropathy (It is characterized by symmetrical
sensory loss, pain at night and during the rest, hyporeflexia, decreased
responce touch, burning of heels and soles. The skin becomes atrophic, dry and
cold, hair loss may be prominent. The decreased response to touch and pain
predisposes to burns and ulcers of the legs and toes.);
-
truncal polyradiculoneuropathy (It is an asymmetric, and characterized
by pain (which is worse at night), paresthesia and hyperesthesia; muscular
weakness involves the muscles of the anterior thigh; reflexes are decreased;
weight loss is common.);
-
truncal monoradiculoneuropathy (It is usually involves thorasic nerves
and the findings are limited to the sensory abnormalities in a radicular
distribution.).
III.
Visceral dysfunction:
Neuropathic
arthropathy (Charcot’s joints)
When you want to lift your arm
or take a step, your brain sends nerve signals to the appropriate muscles.
Internal organs like the heart and bladder are also controlled by nerve
signals, but you do not have the same kind of conscious control over them as
you do over your arms and legs. The nerves that control your internal organs
are called autonomic nerves, and they signal your body to digest food and
circulate blood without your having to think about it. Your body's response to
sexual stimuli is also involuntary, governed by autonomic nerve signals that
increase blood flow to the genitals and cause smooth muscle tissue to relax.
Damage to these autonomic nerves is what can hinder normal function.
1)
gastrointestinal tract:
- esophageal neuropathy (It is characterized
by segmental distribution with low or absent resting pressure in the low or
absent resting pressure in the lower esophageal sphincter and by absence of
peristalsis in the body of the esophagus.);
- diabetic gastroparesis (It leads to the
irregular food absorption and is characterized
by nausea, vomiting, early satiety, bloating and abdomen pain.);
-
involvement of the bowel (It is characterized by diarrhea (mostly at
night time, postural diarrhea), constipation, malabsorption and fecal
incontinence;
2)
cardiovascular system:
-
orthostatic hypotension (It is characterized by dizziness, vertigo,
faintness, and syncope upon assumption of the upright posture and is caused by
failure of peripheral arteriolar constriction.);
-
tachicardia (but it does not occur in response to hypotension because of
sympathetic involvement).
3) urinary
tract:
-
Bladder dysfunction can have a profound effect on quality of life.
Diabetes can damage the nerves that control bladder function. Men and women
with diabetes commonly have bladder symptoms that may include a feeling of
urinary urgency, frequency, getting up at night to urinate often, or leakage of
urine (incontinence). These symptoms have been called overactive bladder. Less
common but more severe bladder symptoms include difficulty urinating and
complete failure to empty (retention). These symptoms are called a neurogenic
bladder. Some evidence indicates that this problem occurs in both men and women
with diabetes at earlier ages than in those without diabetes.
is characterized by painless swelling of the feet
without edema or signs of infection. The foot becomes shorter and wider,
eversion, external rotation, and flattening of the longitudinal arch. This
arthropathy is associated with sensory involvelvement, particularly impairment
of afferent pain proprioceptive impulses.
Diabetic foot.
Appearance of diabetic foot is
caused by a combination of vascular
insufficiency, neuropathy, and infection.
can be
Sensibility
partly decreased or normal decreased or absent
Hypoglycemia
Hypoglycemia, or abnormally
low blood glucose, is a complication of several diabetes treatments. It may
develop if the glucose intake does not cover the treatment. The patient may
become agitated, sweaty, and have many symptoms of sympathetic activation of
the autonomic nervous system resulting in feelings similar to dread and
immobilized panic. Consciousness can be altered, or even lost, in extreme
cases, leading to coma and/or seizures, or even brain damage and death. In
patients with diabetes, this can be caused by several factors, such as too much
or incorrectly timed insulin, too much exercise or incorrectly timed exercise
(exercise decreases insulin requirements) or not enough food (actually an
insufficient amount of glucose producing carbohydrates in food). In most cases,
hypoglycemia is treated with sugary drinks or food. In severe cases, an
injection of glucagon (a hormone with the opposite effects of insulin) or an
intravenous infusion of glucose is used for treatment, but usually only if the
person is unconscious. In hospital, intravenous dextrose is often used.
Coronary artery disease, leading to
angina or myocardial infarction ("heart attack")
Stroke (mainly the ischemic
type)
Peripheral vascular disease,
which contributes to intermittent claudication (exertion-related foot pain) as
well as diabetic foot.
Diabetic myonecrosis ('muscle
wasting')
Diabetic foot, often due to a
combination of neuropathy and arterial disease, may cause skin ulcer and
infection and, in serious cases, necrosis and gangrene. It is the most common
cause of adult amputation, usually of toes and or feet, in the developed world.
http://www.youtube.com/watch?v=vVQjoXN7Nj4&feature=related
Lipids
are water-insoluble organic biomolecules that can be extracted from cells and
tissues by nonpolar solvents, e.g., chloroform, ether, or benzene.
Lipids are an amphiphilic class of hydrocarbon-containing organic compounds. Lipids are categorized by the
fact that they have complicated solvation properties, giving rise to lipid polymorphism. Lipid molecules have these
properties because they consist largely of long hydrocarbon tails which are lipophilic in nature as well as polar
headgroups (e.g. phosphate-based functionality, and/or inositol based functionality). In living
organisms, lipids are used for energy storage, serve as the structural
components of cell membranes, and constitute important signalling
molecules. Although
the term lipid is often used as a synonym for fat, the latter is in fact a subgroup
of lipids called triglycerides.
There are several different families or classes of lipids but all derive
their distinctive properties from the hydrocarbon nature of a major portion of
their structure.
Biological functions of lipids
Biological
molecules that are insoluble in aqueous solutions and soluble in organic solvents
are classified as lipids. The lipids of physiological importance for humans
have four major functions:
Lipids have several important
biological functions, serving
(1) as structural components of membranes,
(2) as storage and transport forms of metabolic fuel,
(3) as a protective coating on the surface of many
organisms, and
(4) 
(5) as cell-surface components concerned in cell
recognition, species specificity, and tissue immunity. Some substances
classified among the lipids have intense biological activity; they include some
of the vitamins and hormones.
Although lipids are a distinct class
of biomolecules, we shall see that they often occur combined, either covalently
or through weak bonds, with members of other classes of biomolecules to yield
hybrid molecules such as glycolipids,
which contain both carbohydrate and lipid groups, "and lipoproteins, which contain both lipids
and proteins. In such biomolecules the distinctive chemical and physical properties
of their components are blended to fill specialized biological functions.
Classification of lipids
Lipids have been classified in
several different ways. The most satisfactory classification is based on their
backbone structures:
1.
Simple
lipids:
1) acylglycerols;
2) steroids;
3) waxes.
2. Complex lipids:
1)
phospholipids
a)
glycerophospholipids;
b) sphingophospholipids.
2) glycolipids
a) glycosylglycerols;
b) glycosphingolipids.
Lipids
usually contain fatty acids as components. Such lipids are called saponifiable lipids since they yield soaps
(salts of fatty acids) on alkaline hydrolysis. The other great group of lipids
which do not contain fatty acids and hence are nonsapomfiable.
Let us first consider the structure
and properties of fatty acids, characteristic components of all the complex lipids.
Fatty Acids
Fatty acids and glycerides
Fatty acids fill two major roles in the body:
·
1. as the
components of more complex membrane lipids.
·
2. as the
major components of stored fat in the form of triacylglycerols.
Fatty acids are long-chain hydrocarbon molecules
containing a carboxylic acid moiety at one end. The numbering of carbons in
fatty acids begins with the carbon of the carboxylate group. At physiological
pH, the carboxyl group is readily ionized, rendering a negative charge onto fatty
acids in bodily fluids.
Fatty acids that contain no
carbon-carbon double bonds are termed saturated fatty acids; those that contain
double bonds are unsaturated fatty acids. The numeric designations used for fatty
acids come from the number of carbon atoms, followed by the number of sites of
unsaturation (eg, palmitic acid is a 16-carbon fatty acid with no unsaturation
and is designated by 16:0). The site of unsaturation in a fatty acid is
indicated by the symbol and the number of the first carbon of the double bond
(e.g. palmitoleic acid is a 16-carbon fatty acid with one site of unsaturation
between carbons 9 and 10, and is designated by 16:19).
Saturated fatty acids of less than eight carbon atoms
are liquid at physiological temperature, whereas those containing more than ten
are solid. The presence of double bonds in fatty acids significantly lowers the
melting point relative to a saturated fatty acid.
The majority of body fatty acids
are acquired in the diet. However, the lipid biosynthetic capacity of the body
(fatty acid synthase and other fatty acid modifying enzymes) can supply the
body with all the various fatty acid structures needed. Two key exceptions to
this are the highly unsaturated fatty acids know as linoleic acid and linolenic
acid, containing unsaturation sites beyond carbons 9 and 10. These two fatty
acids cannot be synthesized from precursors in the body, and are thus
considered the essential fatty acids;
essential in the sense that they must be provided in the diet. Since plants are
capable of synthesizing linoleic and linolenic acid humans can aquire these
fats by consuming a variety of plants or else by eating the meat of animals
that have consumed these plant fats.
Chemically, fatty acids can be
described as long-chain monocarboxylic acids and have a general structure of CH3(CH2)nCOOH.
The length of the chain usually ranges from 12 to 24, always with an even
number of carbons. When the carbon chain contains no double bonds, it is a saturated chain. If it contains one or more
such bonds, it is unsaturated. The presence of double bonds generally reduces
the melting point of fatty acids. Furthermore, unsaturated fatty acids can
occur either in cis or trans geometric isomers. In naturally occurring fatty acids, the double bonds
are in the cis-configuration.
Glycerides are lipids possessing a glycerol (propan-1, 2, 3-triol) core structure with one or
more fatty acyl groups, which are fatty acid-derived chains attached to the
glycerol backbone by ester linkages. Glycerides with three acyl groups (triglycerides or neutral fats) are the main storage form of fat in
animals and plants.
An important type of
glyceride-based molecule found in biological
membranes, such as
the cell's plasma membrane and the intracellular membranes of
organelles, are the phosphoglycerides or glycerophospholipids. These are phospholipids that contain a glycerol core
linked to two fatty acid-derived "tails" by ester or, more rarely, ether linkages and to one
"head" group by a phosphate ester linkage. The head groups of
the phospholipids found in biological membranes are phosphatidylcholine (also
known as PC, and lecithin), phosphatidylethanolamine (PE),
phosphatidylserine and phosphatidylinositol (PI). These phospholipids are subject to a variety of functions in the cell:
for instance, the lipophilic and polar ends can be released from specific
phospholipids through enzyme-catalysed hydrolysis to generate secondary
messengers involved
in signal transduction. In the case of phosphatidylinositol, the head group can be enzymatically modified by the
addition of one, two or three phosphate groups, this constituting another
mechanism of cell signalling. While phospholipids are the major component of
biological membranes, other non-glyceride lipid components like sphingolipids and sterols (such as cholesterol in animal cell membranes) are also found in
biological membranes.
A biological membrane is a form of lipid bilayer, as
is a liposome. Formation of lipid bilayers is an
energetically-favoured process when the glycerophospholipids described above
are in an aqueous environment. In an aqueous system, the polar heads of lipids
orientate towards the polar, aqueous environment, while the hydrophobic tails
minimise their contact with water. The
lipophilic tails of lipids (U) tend to cluster together, forming a lipid bilayer (1) or a micelle (2). Other aggregations are also
observed and form part of the polymorphism of amphiphile (lipid) behaviour. The polar heads
(P) face the aqueous environment, curving away from the water. Phase behaviour is a complicated area within
biophysics and is the subject of current academic research.
Micelles and bilayers form in the polar medium by a
process known as the lipophilic effect. When
dissolving a lipophilic or amphiphilic substance in a polar environment, the
polar molecules (i.e. water in an aqueous solution) become more ordered around
the dissolved lipophilic substance, since the polar molecules cannot form hydrogen bonds to the lipophilic areas of the amiphphile. So, in an aqueous environment the
water molecules form an ordered "clathrate" cage around the dissolved
lipophilic molecule.
The self-organisation depends on the concentration of the lipid present
in solution. Below the critical micelle
concentration, the
lipids form a single layer on the liquid surface and are (sparingly) dispersed
in the solution. At the first critical micelle concentration (CMC-I), the
lipids organise in spherical micelles, at given points above this
concentration, other phases are observed (see lipid polymorphism).
Self-organization
of phospholipids. A lipid bilayer is shown on the left and a micelle on
the right.
http://www.youtube.com/watch?v=CLaAPl-_rRM&NR=1
Although fatty acids occur in very large amounts as
building-block components of the saponifiable lipids, only traces occur in free
(unesterified) form in cells and tissues. Well over 100 different kinds of
fatty acids have been isolated from various lipids of animals, plants, and
microorganisms. All possess a long hydrocarbon chain and a terminal carboxyl
group. The hydrocarbon chain may be saturated, as in palmitic acid, or it may have one or more double bonds, as in oleic acid; a few fatty acids contain
triple bonds. Fatty acids differ from each other primarily in chain
length and in the number and position of their unsaturated bonds. They are
often symbolized by a shorthand notation that designates the length of the
carbon chain and the number, position, and configuration of the double bonds.
Thus palmitic acid (16 carbons, saturated) is symbolized 16:0 and oleic acid
[18 carbons and one double bond (cis) at carbons 9 and 10] is symbolized 18:1.
It is understood that the double bonds are cis (see below) unless indicated
otherwise.
Some
generalizations can be made on the different fatty acids of higher plants and
animals. The most abundant have an even number of carbon atoms with chains
between 14 and 22 carbon atoms long, but those with 16 or 18 carbons predominate.
The most common among the saturated fatty acids are palmitic acid (Cis) and
stearic acid (Cis) and among the unsaturated fatty acids oleic acid (Cis).
Unsaturated fatty acids predominate over the saturated ones, particularly in
higher
plants and in animals living at low temperatures. Unsaturated fatty
acids have lower
melting points than saturated fatty acids of the same chain length. In most
monounsaturated (monoenoic) fatty acids of higher organisms there is a double
bond between carbon atoms 9 and
There are two kinds of fats,
saturated and unsaturated. Unsaturated fats have at least one
double bond in one of the fatty acids. A double bond happens when two electrons
are shared or exchanged in a bond. They are much stronger than single bonds. Saturated
fats have no double bonds.
Fats have a lot of energy stored up in their molecular bonds. That's why the
human body stores fat as an energy source. When it needs extra fuel, your body
breaks down the fat and uses the energy. Where one molecule of sugar only gives
a small amount of energy, a fat molecule gives off many times more.
Some naturally occuring fatty acids
|
Symbol |
Structure
|
Systemic name |
Common name |
Saturated fatty acid
|
|||
|
С12:0 |
СН3(СН2)10СООН |
n-Dodecanoic |
Lauric |
|
С14:0 |
СН3(СН2)12СООН |
n-Tetradecanoic |
Myristic |
|
С16:0 |
СН3(СН2)14СООН |
n-Hexadecanoic |
Palmitic |
|
С18:0 |
СН3(СН2)16СООН |
n-Octadecanoic |
Stearic |
|
С20:0 |
СН3(СН2)18СООН |
n-Eicosanoic |
Arachidic |
|
С22:0 |
СН3(СН2)20СООН |
n-Docosanoic |
Begenic |
|
С24:0 |
СН3(СН2)22СООН |
n-Tetracosanoic |
Lignoceric |
Unsaturated monoenic
fatty acid
|
|||
|
С16:1 |
СН3(СН2)5СН=СН(СН2)7СООН |
|
Palmitooleic |
|
С18:1 |
СН3(СН2)7СН=СН(СН2)7СООН |
|
Oleic |
Unsaturated polienic fatty acid
|
|||
|
С18:2 |
СН3(СН2)4(СН=СНСН2)2(СН2)6СООН |
|
Linoleic |
|
С18:3 |
СН3СН2(СН=СНСН2)3(СН2)6СООН |
|
Linolenic |
|
С20:4 |
СН3(СН2)4(СН=СНСН2)4(СН2)2СООН |
|
Arachidonic |
All Lipids are hydrophobic: that’s the one
property they have in common. This group of molecules includes fats and oils,
waxes, phospholipids, steroids (like cholesterol), and some other related
compounds.
Structure of Fatty Acids
|
|
|
Fats and oils are made from two kinds of
molecules: glycerol (a type of
alcohol with a hydroxyl group on each of its three carbons) and three fatty acids joined by dehydration synthesis.
Since there are three fatty acids attached, these are known as triglycerides. “Bread” and pastries from a
“bread factory” often contain mono- and diglycerides as “dough conditioners.” Can you figure out what these molecules would
look like? The main distinction between fats and oils is whether they’re
solid or liquid at room temperature, and this, as we’ll soon see, is based on
differences in the structures of the fatty acids they contain. |
Essential
fatty acids
When weanling or immature rats
are placed on a fat-free diet, they grow poorly, develop a scaly skin, lose
hair, and ultimately die with many pathological signs. When linoleic acid is present in the diet,
these conditions do not develop. Linolenic
acid and arachidonic acid also prevent these symptoms. Saturated and
monounsaturated fatty acids are inactive. It has been concluded that mammals
can synthesize saturated and monounsaturated fatty acids from other precursors
but are unable to make linoleic and linolenic acids. Fatty acids required in
the diet of mammals are called essential
fatty acids. The most abundant essential fatty acid in mammals is linoleic acid, which makes up from 10 to
20 percent of the total fatty acids of their triacylglycerols and
phosphoglycerides. Linoleic and linolenic acids cannot be synthesized by
mammals but must be obtained from plant sources, in which they are very
abundant. Linoleic acid is a necessary precursor in mammals for the
biosynthesis of arachidonic acid,
which is not found in plants.
The terms saturated,
mono-unsaturated, and poly-unsaturated refer to the number of
hydrogens attached to the hydrocarbon tails of the fatty acids as compared to the
number of double bonds between carbon atoms in the tail. Fats, which are mostly
from animal sources, have all single bonds between the carbons in their fatty
acid tails, thus all the carbons are also bonded to the maximum number of
hydrogens possible. Since the fatty acids in these triglycerides contain the
maximum possible amouunt of hydrogens, these would be called saturated fats. The hydrocarbon chains in these fatty acids are, thus,
fairly straight and can pack closely together, making these fats solid at room
temperature. Oils, mostly from plant sources, have some double bonds between
some of the carbons in the hydrocarbon tail, causing bends or “kinks” in the
shape of the molecules. Because some of the carbons share double bonds, they’re
not bonded to as many hydrogens as they could if they weren’t double bonded to
each other. Therefore these oils are called unsaturated fats. Because of the kinks in the hydrocarbon tails,
unsaturated fats can’t pack as closely together, making them liquid at room temperature.
Many people have heard that the unsaturated fats are “healthier” than the
saturated ones. Hydrogenated vegetable
oil (as in shortening and commercial peanut butters where a solid
consistency is sought) started out as “good” unsaturated oil. However, this
commercial product has had all the double bonds artificially broken and
hydrogens artificially added (in a chemistry lab-type setting) to turn it into
saturated fat that bears no resemblance to the original oil from which it came
(so it will be solid at room temperature).
Although the specific functions of
essential fatty acids in mammals were a mystery for many years, one function
has been discovered. Essential fatty acids are necessary precursors in the
biosynthesis of a group of fatty acid derivatives called prostaglandins, hormonelike compounds which in trace amounts have
profound effects on a number of important physiological activities.
Physical and chemical properties of fatty acids
Saturated and unsaturated
fatty acids have quite different conformations. In saturated fatty acids, the
hydrocarbon tails are flexible and can exist in a very large number of conformations
because each single bond in the backbone has complete freedom of rotation.
Unsaturated fatty acids, on the other hand, show one or more rigid kinks contributed
by the nonrotating double bond(s).
Unsaturated fatty acids
undergo addition reactions at their double bonds. Quantitative titration with
halogens, e.g., iodine or bromine, can yield information on the relative number
of double bonds in a given sample of fatty acids or lipid.
Triacylglycerols (Triglycerides)
Fat is also known as a
triglyceride. It is made up of a molecule known as glycerol
that is connected to one, two, or three fatty acids. Glycerol is the basis of
all fats and is made up of a three-carbon chain. It connects the fatty
acids together. A fatty acid is a long chain of carbon atoms connected
to each other.
Fatty acid esters of the
alcohol glycerol are called acylglycerols
or glycerides; they are
sometimes referred to as "neutral
fats," a term that has become archaic. When all three hydroxyl groups
of glycerol are esterified with fatty acids, the structure is called a triacylglycerol:
Although the name
"triglyceride" has been traditionally used to designate these
compounds, an international nomenclature commission has recommended that this
chemically inaccurate term no longer be used. Triacylglycerols are the most
abundant family of lipids and the major components of depot or storage lipids
in plant and animal cells. Triacylglycerols that are solid at room temperature
are often referred to as "fats" and those which are liquid as
"oils." Diacylgiycerols
(also called diglycerides) and monoacylgiycerols (or monoglycerides) are
also found in nature, but in much smaller amounts.
Triacylglycerols occur in many
different types, according to the identity and position of the three fatty acid
components esterified to glycerol. Those with a single kind of fatty acid in
all three positions, called simple triacylglycerols, are named after the fatty
acids they contain. Examples are tristearoylglycerol,
tripalmitoylglycerol, and trioleoylglycerol; the trivial
and more commonly used names are tristearin,
tripalmitin, and trioiein, respectively. Mixed triacylglycerols
contain two or more different fatty acids. The naming of mixed triacylglycerols
can be illustrated by the example of 1-palmitoyldi-stearoylglycerol
(trivial name, 1-palmitodistearin).
Most natural fats are extremely complex mixtures of simple and mixed triacylglycerols.
Properties of
triacylglycerols
The melting
point of triacylglycerols is determined by their fatty acid components. In
general, the melting point increases with the number and length of the saturated
fatty acid components. For example, tripalmitin and tristearin are solids at
body temperature, whereas triolein and trilinolein are liquids. All
triacylglycerols are insoluble in water and do not tend by themselves to form
highly dispersed micelles. However,
diacylglycerols and monoacylglycerols have appreciable polarity because of
their free hydroxyl groups and thus can form micelles. Diacyl- and
monoacylglycerols find wide use in the food industry in the production of more
homogeneous and more easily processed foods; they are completely digestible and
utilized biologically. Acylglycerols are soluble in ether, chloroform,
benzene, and hot ethanol. Their specific gravity is lower than that of water. Acylglycerols
undergo hydrolysis when boiled with acids or bases or by the action of lipases,
e.g., those present in pancreatic juice. Hydrolysis with alkali, called
saponification, yields a mixture of soaps and glycerol.
Steroids
Steroids
occur in animals in something called hormones. The basis of a steroid
molecule is a four-ring structure, one with five carbons and three with six
carbons in the rings. You may have heard of steroids in the news. Many body
builders and athletes use anabolic steroids to build muscle mass. The steroids
make their body want to add more muscle than they normally would be able to. The body builders wind up stronger and bulkier (but
not faster).
Never take drugs to enhance your body. Those body builders are actually hurting
their bodies. They can't see it because it is slowly destroying their internal
organs and not the muscles. When they get older, they can have kidney and liver
problems. Some even die.
The important class of lipids called steroids are actually metabolic
derivatives of terpenes, but they are customarily treated as a separate group.
Steroids may be recognized by their tetracyclic skeleton, consisting of three
fused six-membered and one five-membered ring, as shown in the diagram to the
right. The four rings are designated A, B, C & D as noted, and the peculiar
numbering of the ring carbon atoms (shown in red) is the result of an earlier
misassignment of the structure. The substituents designated by R are
often alkyl groups, but may also have functionality. The R group at the A:B
ring fusion is most commonly methyl or hydrogen, that at the C:D fusion is
usually methyl. The substituent at C-17 varies considerably, and is usually
larger than methyl if it is not a functional group. The most common locations
of functional groups are C-3, C-4, C-7, C-11, C-12 & C-17. Ring A is
sometimes aromatic. Since a number of tetracyclic triterpenes also have this
tetracyclic structure, it cannot be considered a unique identifier.
Steroids are widely distributed in
animals, where they are associated with a number of physiological processes.
Examples of some important steroids are shown in the following diagram.
Different kinds of steroids will be displayed by clicking the "Toggle
Structures" button under the diagram. Norethindrone is a synthetic
steroid, all the other examples occur naturally. A common strategy in pharmaceutical chemistry is to take a natural
compound, having certain desired biological properties together with undesired
side effects, and to modify its structure to enhance the desired
characteristics and diminish the undesired. This is sometimes accomplished by
trial and error.
The generic steroid structure drawn above has seven chiral stereocenters
(carbons 5, 8, 9, 10, 13, 14 & 17), which means that it may have as many as
128 stereoisomers. With the exception of C-5, natural steroids generally have a
single common configuration. This is shown in the last of the toggled displays,
along with the preferred conformations of the rings.
Chemical studies of the steroids were very important
to our present understanding of the configurations and conformations of
six-membered rings. Substituent groups at different sites on the tetracyclic
skeleton will have axial or equatorial orientations that are fixed because of
the rigid structure of the trans-fused rings. This fixed orientation influences
chemical reactivity, largely due to the greater steric hindrance of axial
groups versus their equatorial isomers. Thus an equatorial hydroxyl group is
esterified more rapidly than its axial isomer.
Steroids are complex ethers of cyclic spirits sterols and fatty acids. Sterols are
derivatives of the saturated tetracylic hydrocarbon
cyclopentanoperhydrophenanthrene:
Cyclopentanoperhydrophenanthrene Cholesterol
The general structure of cholesterol
consists of two six-membered rings side-by-side and sharing one side in common,
a third six-membered ring off the top corner of the right ring, and a
five-membered ring attached to the right side of that.
The central core of this molecule, consisting of four fused rings, is
shared by all steroids, including
estrogen (estradiol), progesterone, corticosteroids such as cortisol
(cortisone), aldosterone, testosterone, and Vitamin D. In the various types of
steroids, various other groups/molecules are attached around the edges. Know
how to draw the four rings that make up the central structure.
Cholesterol is not a “bad guy!” Our bodies make about
Many people have hear the claims that egg yolk
contains too much cholesterol, thus should not be eaten. An interesting study
was done at Purdue University a number of years ago to test this. Men in one
group each ate an egg a day, while men in another group were not allowed to eat
eggs. Each of these groups was further subdivided such that half the men got
“lots” of exercise while the other half were “couch potatoes.” The results of
this experiment showed no significant difference in blood cholesterol levels
between egg-eaters and non-egg-eaters while there was a very significant
difference between the men who got exercise and those who didn’t.
A great many
different steroids, each with a distinctive function or activity, have been
isolated from natural sources. Steroids differ in the number and position of
double bonds, in the type, location, and number of substituent functional
groups, in the configuration of the bonds between the substituent groups and
the nucleus, and in the configuration of the rings in relation to each other. Cholesterol
is the most abundant steroid in animal tissues. Cholesterol and lanosterol
are members of a large subgroup of steroids called the sterols. They are steroid alcohols containing a hydroxyl group
at carbon 3 of ring A and a branched aliphatic chain of eight or more carbon
atoms at carbon 17. They occur either as free alcohols or as long-chain fatty
acid esters of the hydroxyl group at carbon 3; all are solids at room
temperature. Cholesterol melts at
Cholesterol is the precursor
of many other steroids in animal tissues, including the bile acids, detergentlike compounds that aid in
emulsification and absorption of lipids in the intestine; the androgens, or male sex hormones; the estrogens, or female sex
hormones; the progestational hormone progesterone; and the adrenocortical hormones. Among the most important steroids are a
group of compounds having vitamin D activity.
Waxes
Waxes are water-insoluble,
solid esters of higher fatty acids with long-chain monohydroxylic fatty
alcohols or with sterols. They are soft and pliable when warm but hard when
cold. Waxes are found as protective coatings on skin, fur, and feathers, on
leaves and fruits of higher plants, and on the exoskeleton of many insects. The
major components of beeswax are palmitic acid esters of long-chain fatty
alcohols with 26 to 34 carbon atoms. Lanolin,
or wool fat, is a mixture of fatty acid esters of the sterols lanosterol and
agnosterol.
Waxes are used to
coat and protect things in nature. Bees make wax. Your ears make wax. Plant
leaves even have wax on the outside of their leaves. It can be used for
structures such as the bees' honeycombs. Waxes can also be used for protection.
Plants use wax to stop evaporation
of water from their leaves.
Prostaglandins Thromboxanes & Leukotrienes
The members of this group of structurally related
natural hormones have an extraordinary range of biological effects. They can
lower gastric secretions, stimulate uterine contractions, lower blood pressure,
influence blood clotting and induce asthma-like allergic responses. Because
their genesis in body tissues is tied to the metabolism of the essential fatty
acid arachadonic acid (5,8,11,14-eicosatetraenoic acid) they are classified as eicosanoids. Many properties of the
common drug asprin result from its effect on the cascade of reactions
associated with these hormones.
The
metabolic pathways by which arachidonic acid is converted to the various
eicosanoids are complex and will not be discussed here. A rough outline of some
of the transformations that take place is provided below. It is helpful to view
arachadonic acid in the coiled conformation shown in the shaded box.
Phospholipids
http://www.youtube.com/watch?v=PoolWjqoyO0
Glycerophospholipids
(phosphoglycerides)
The basic
structure of phospolipids is very similar to that of the triacylglycerides
except that C-3 (sn3)of the glycerol
backbone is esterified to phosphoric acid. The building block of the
phospholipids is phosphatidic acid which results when the X substitution in the
basic structure shown in the Figure below is a hydrogen atom. Substitutions
include ethanolamine (phosphatidylethanolamine), choline (phosphatidylcholine,
also called lecithins), serine (phosphatidylserine), glycerol
(phosphatidylglycerol), myo-inositol
(phosphatidylinositol, these compounds can have a variety in the numbers of
inositol alcohols that are phosphorylated generating
polyphosphatidylinositols), and phosphatidylglycerol.
Phosphoglycerides are characteristic
major components of cell membranes; only very small amounts of
phosphoglycerides occur elsewhere in cells.
Phospholipids
are made from glycerol, two fatty acids, and (in place of the third fatty acid)
a phosphate
group with some other molecule
attached to its other end. The hydrocarbon tails of the fatty acids are still
hydrophobic, but the phosphate group end of the molecule is hydrophilic because
of the oxygens with all of their pairs of unshared electrons. This means that
phospholipids are soluble in both water and oil.
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An emulsifying agent is a
substance which is soluble in both oil and water, thus enabling the two to mix.
A “famous” phospholipid is lecithin which is found in egg yolk and soybeans. Egg yolk is mostly water but
has a lot of lipids, especially cholesterol, which are needed by the developing
chick. Lecithin is used to emulsify the
lipids and hold them in the water as an emulsion.
Lecithin is the basis of the classic emulsion known as mayonnaise.
http://www.youtube.com/watch?v=7k2KAfRsZ4Q&feature=related
Our cell membranes are made
mostly of phospholipids arranged in a double
layer with the tails from both layers “inside”
(facing toward each other) and the heads facing “out” (toward the watery
environment) on both surfaces.
In phosphoglycerides one of the
primary hydroxyl groups of glycerol is esterified to phosphoric acid; the other
hydroxyl groups are esterified to fatty acids. The parent compound of the
series is thus the phosphoric ester of glycerol.
Because
phosphoglycerides possess a polar head in addition to their nonpolar
hydrocarbon tails, they are called amphipathic
or polar lipids. The different types
of phosphoglycerides differ in the size, shape, and electric charge of their
polar head groups.
The parent
compound of the phosphoglycerides is phosphatidic
acid, which contains no polar alcohol head group. It occurs in only very
small amounts in cells, but it is an important intermediate in the biosynthesis
of the phosphoglycerides.
posphatidic acid
The most abundant phosphoglycerides
in higher plants and animals are phosphatidylethanoamme
and phosphatidylchohne, which contain
as head groups the amino alcohols ethanoiamine
and choline, respectively.
(The new names recommended for these phosphoglycerides are ethanolamine
phosphoglyceride and choline phosphoglyceride, but they have not yet
gained wide use. The old trivial names are cephalin
and lecithin, respectively.) These
two phosphoglycerides are major components of most animal cell membranes.
In phosphqtidylserine, the hydroxyl
group of the amino acid L-serine is esterified to the phosphoric acid.
Closely related to
phosphatidylglycerol is the more complex lipid cardiolipin, also called diphosphatidylglycerol,
which consists of a molecule of phosphatidylglycerol in which the 3'-hydroxyl
group of the second glycerol moiety is esterified to the phosphate group of a
molecule of phosphatidic acid. The backbone of cardiolipin thus consists of three molecules of glycerol joined by
two phosphodiester bridges; the two hydroxyl groups of both external glycerol
molecules are esterified with fatty acids. Cardiolipin
is present in large amounts in the inner membrane of mitochondria; it was first
isolated from heart muscle, in which mitochondria are abundant.
http://www.youtube.com/watch?v=kOTRNFZHmTI&feature=related
Lipid
Soluble Vitamins
The essential dietary
substances called vitamins are commonly
classified as "water soluble" or "fat soluble". Water
soluble vitamins, such as vitamin C, are rapidly eliminated from the body and
their dietary levels need to be relatively high. The recommended daily
allotment (RDA) of vitamin C is 100 mg, and amounts as large as 2 to
Vitamin A 800 μg ( upper
limit ca. 3000 μg)
Vitamin D 5 to 10 μg ( upper
limit ca. 2000 μg)
Vitamin E 15 mg ( upper limit ca.
Vitamin K 110 μg ( upper
limit not specified)
From this data it is clear that vitamins A and D, while essential to
good health in proper amounts, can be very toxic. Vitamin D, for example, is
used as a rat poison, and in equal weight is more than 100 times as poisonous
as sodium cyanide. From the structures shown here, it should be clear that
these compounds have more than a solubility connection with lipids. Vitamins A
is a terpene, and vitamins E and K have long terpene chains attached to an
aromatic moiety. The structure of vitamin D can be described as a steroid in
which ring B is cut open and the remaining three rings remain unchanged. The
precursors of vitamins A and D have been identified as the tetraterpene
beta-carotene and the steroid ergosterol, respectively.
Properties of
phosphoglycerides
Phosphoglycerides are soluble in
most nonpolar solvents containing some water and are best extracted from cells
and tissues with chloroform-methanol mixtures. When phosphoglycerides are
placed in water, they appear to dissolve, but only very minute amounts go into
true solution; most of the "dissolved" lipid is in the form of
micelles.
Phosphoglycerides have variations in the size, shape, polarity, and
electric charge and it plays a significant role in the structure of various
types of cell membranes.
Phosphoglycerides can be hydrolyzed by
specific phospholipases, which have
become important tools in the determination of phosphoglyceride structure.
Phospholipase A1 specifically removes the fatty acid from the 1 position and
phospholipase A2 from the 2 position. Removal of one fatty acid molecule from
a phosphoglyceride yields a lysophosphoglyceride,
e.g., lysophosphatidyl-ethanolamine. Lysophosphoglycerides are
intermediates in phosphoglyceride metabolism but are found in cells or tissues
in only very small amounts; in high concentrations they are toxic and injurious
to membranes. Phospholipase B can bring about successive removal of the two
fatty acids of phosphoglycerides. Phospholipase C hydrolyzes the bond between
phosphoric acid and glycerol, while phospholipase D removes the polar head
group to leave a phosphatidic acid.
Sphingophospholipids
Sphingolipids are composed of a backbone of sphingosine which is derived
itself from glycerol. Sphingosine is N-acetylated by a variety of fatty acids
generating a family of molecules referred to as ceramides. Sphingolipids
predominate in the myelin sheath of nerve fibers. Sphingomyelin is an abundant
sphingolipid generated by transfer of the phosphocholine moiety of
phosphatidylcholine to a ceramide, thus sphingomyelin is a unique form of a phospholipid.
The other
major class of sphingolipids (besides the sphingomyelins) are the
glycosphingolipids generated by substitution of carbohydrates to the sn1 carbon of the glycerol backbone of a
ceramide. There are 4 major classes of glycosphingolipids:
n
Cerebrosides: contain a single moiety, principally galactose.
n
Sulfatides: sulfuric acid esters of galactocerebrosides.
n
Globosides: contain 2 or more sugars.
n
Gangliosides: similar to globosides except also contain sialic acid.
Sphingolipids
Sphingophospholipids,
complex lipids containing as their backbone sphingosine,
are important membrane components in both plant and animal cells. They are
present in especially large amounts in brain and nerve tissue. Only trace
amounts of sphingophospholipids are found in depot fats. All
sphingophospholipids contain four characteristic building-block components: one
molecule of a fatty acid, one molecule of sphingosine,
phosphoric acid and a polar head group, which in some sphingolipids is very
large and complex.
The most abundant
sphingophospholipids in the tissues of higher animals are sphingomyelins, which
contain phosphorylethanolamine or phosphorylcholine as their polar head groups,
esterified to the 1-hydroxyl group of ceramide. Sphingomyelins have physical
properties very similar to those of phosphatidylethanolamine and
phosphatidylcholine.
Glycolipids
Glycosylglycerols
Glycosyldiqcylglycerols contain a sugar in glycosidic linkage with the unesterified 3-hydroxyl
group of diacylglycerols. A common example is galactosyldiacylglycerol, found in higher
plants and also in neural tissue of vertebrates.
Glycosphingolipids
Neutral glycosphingolipids
This class of glycolipids
contains one or more neutral sugar residues as their polar head groups and thus
has no electric charge; they are called neutral glycosphingolipids. The
simplest of these are the cerebrosides,
which contain as their polar head group a monosaccharide bound in
beta-glycosidic linkage to the hydroxyl group of ceramide. The cerebrosides of the brain and nervous system contain
D-galactose and are therefore called galactocerebrosides.
Cerebrosides are also present in much smaller amounts in nonneural tissues of
animals, where, because they usually contain D-glucose instead of D-galactose,
they are called glucocerebrosides.
Sulfate esters of
galactocerebrosides (at the 3 position of the D-galactose) are also present in
brain tissue; they are called sulfotides.
The neutral glycosphingolipids are important
cell-surface components in animal tissues. Their nonpolar tails presumably
penetrate into the lipid bilayer structure of cell membranes, whereas the polar
heads protrude outward from the surface. Some of the neutral glycosphingolipids
are found on the surface of red blood cells and give them blood-group
specificity.
Acidic
glycosphingolipids (gangliosides)
Gangliosides contain in their oligosaccharide
head groups one or more residues of a sialic acid, which gives the polar head
of the gangliosides a net negative charge at pH 7.0. The sialic acid usually
found in human gangliosides is N-acetylneuraminic
acid. Gangliosides are most abundant in the gray matter of the brain, where
they constitute 6 percent of the total lipids, but small amounts are also found
in nonneural tissues.
Function of glycosphingolipids
Although glycosphingolipids are only
minor constituents of membranes, they appear to be extremely important in a
number of specialized functions. Because gangliosides are especially abundant
in nerve endings, it has been suggested that they function in the transmission
of nerve impulses across synapses. They are also believed to be present at
receptor sites for acetylcholine and other neurotransmitter substances. Some of
the cell-surface glycosphingolipids are concerned not only in blood-group
specificity but also in organ and tissue specificity. These complex lipids are
also involved in tissue immunity and in cell-cell recognition sites fundamental
to the development and structure of tissues. Cancer cells, for example, have
characteristic glycosphingolipids different from those in normal cells.
The most important
derivatives of lipids
The lipids discussed up to
this point contain fatty acids as building blocks, which can be released on
alkaline hydrolysis. The simple lipids contain no fatty acids. They occur in
smaller amounts in cells and tissues than the complex lipids, but they include
many substances having profound biological activity—vitamins, hormones, and
other highly specialized fat-soluble biomolecules.
Prostaglandins are a family of
fatty acid derivatives which have a variety of potent biological activities of
a hormonal or regulatory nature. Prostaglandins function as regulators of
metabolism in a number of tissues and in a number of ways.
All the natural prostaglandins
are biologically derived by cyclization of 20-carbon unsaturated fatty acids,
such as arachidonic acid, which is formed from the essential fatty acid
linoleic acid. The prostaglandins differ from each other with respect to their
biological activity, although all show at least some activity in lowering
blood pressure and inducing smooth muscle to contract. Some, like PGE2,
antagonize the action of certain hormones. PGE2 and PGE2a may find clinical use in inducing labor and bringing about therapeutic
abortion.
Digestion of fats
By
far the most common of the diet are the neutral fats, also known as triglycerides, each molecule of which is
composed of a glycerol nucleus and three fatty acids, as illustrated. Neutral fat
is found in food of both animal and and plant origin. In the usual diet are
also small quantities of phospholipids, cholesterol, and cholesterol esters.
Digestion of fats in the intestine. A small amount of short chain triglycerides is
digested in the stomach by gastric
lipase.
Emulsification of fat by bile acids. The first in fat digestion is to break the fat
globules into s sizes so that the water-soluble digestive enzymes act on the
globule surfaces. This process is called emulsification
of the
fat, and it
is achieved under 
the
presence of bile acids. Bile contain
a large quantity of bile salts,
mainly in the form of ionized sodium salts.
The carboxyl and other parts of the bile
salt molecule are highly soluble in water, whereas most of the sterol portion
of the bile is highly soluble in fat. Therefore, the fat-soluble portion of the
bile salt dissolves in the surface layer of the fat globule and polar portion
of the bile salt is soluble in the surrounding fluids. This effect decreases
the interfacial tension of the fat. When the interfacial tension of a globule
is low, globule is broken up into many minute particles. The total surface area
of the particles in the intestinal contents is inversely proportional to the
diameters of the particles. The lipases are water-soluble compounds and can act
on the fat globules only on their surfaces. Consequently, it can be readily
understood how important detergent function of bile salts is for the digestion
of fats.
Digestion of fats by pancreatic
lipase. The most
important enzyme for the digestion of fats is pancreatic lipase in the pancreatic juice. However, the cells of
the small intestine also contain a minute quantity of lipase known as enteric lipase. Both liiese act alike to cause hydrolysis of fat.
Products of fat digestion. Most of the triglycerides of the diet are
split into free fatty acids and monoglycerides.
Role
of bile salts in accelerating fat digestion — formation of micelles. The hydrolysis of triglycerides highly
reversible process; therefore, accumulation of monoglycerides and free fatty
acids very quickly blocks further digestion. The bile salts play an important role in removing the monoglycerides
and free fatty acids from the
vicinity of the digesting fat globules almost as rapidly as these end-products
of digestion are formed. This occurs in the following way: bile
salts have the propensity to form micelles, which are small spherical globules composed of 20 to 40 molecules of
bile salt. These develop because each
bile salt molecule is composed of a sterol nucleus, most of which is highly
fat-soluble, and a polar group that is highly water-soluble. The sterol nuclei of the 20 to 40 bile salt
molecules of the micelle aggregate together to form a small fat globule in the
middle of the micelle. This
aggregation causes the polar groups to project outward to cover the surface of
the micelle During triglyceride
digestion, as rapidly as the monoglycerides and free fatty acids are formed
they become dissolved in the fatty portion of the micelles, which immediately
reduces these end-products of digestion in the vicinity of the digesting fat
globules. The bile salt micelles also
act as a transport medium to carry the monoglycerides and the free fatty acids,
both of which would otherwise be relatively insoluble, to the brush borders of
the epithelial cells. There the
monoglycerides and free fatty acids are absorbed. On delivery of these substances to the brush border, the bile salts are
again released 
back into the chyme to be used again and again
for this "ferrying" process.
Digestion of Cholesterol Esters and
Phospholipids. Most of the cholesterol in
the diet is in the form of cholesterol esters, which are combinations of free
cholesterol and one molecule of fatty acid. And phospholipids also contain
fatty acid chains within their molecules. Both the cholesterol esters and the phospholipids are hydrolyzed by lipases in the pancreatic secretion that free the fatty acids — the
enzyme cholesterol ester hydrolase to
hydrolyze the cholesterol ester and phospholipase A to hydrolyze the phospholipid.
The bile salt micelles play
identically the same role in "ferrying" free cholesterol as they play
in "ferrying" monoglycerides and free fatty acids. Indeed,
this role of the bile salt micelles is absolutely essential to the absorption
of cholesterol because essentially no cholesterol is absorbed without the
presence of bile salts. On the other
hand, as much as 60 per cent of the triglycerides can be digested and absorbed
even in the absence of bile salts.
Absorption of fats
Monoglycerides and fatty acids - both of digestive
end-products - become dissolved in the lipid portion of the micelles. Because
of the molecular dimension of these micelles, only 2.5 nanometers, and also
because of their highly charged, they are soluble in the chyme. Micelles
contact with the surfaces of the brush border even penetrating into the
recesses , agitating microvilli. 
The micelles then
diffuse back through the chyme and absorb still more monoglycerides and fatty acids, and
similarly transport these also to the epithelial cells. Thus, the bile acids
perform a "ferrying" function, which is highly important for fat
absorption. In the presence of an
abundance of bile acids, approximately 97 per cent of the fat is absorbed; in
the absence of bile acids, only 50 to 60 per cent is normally absorbed.
The mechanism for
absorption of the monoglycerides and fatty acids through the brush border is
based entirely on the fact that both these substances are highly
lipid-soluble. Therefore, they become dissolved in the
membrane and simply diffuse to the interior of the cell. The undigested
triglycerides and the diglycerides are both also highly soluble in the lipid
membrane of the epithelial cell. However,
only small quantities of these are normally absorbed because the bile acid
micelles will not dissolve either triglycerides or diglycerides and therefore
will not ferry them to the epithelial membrane.
After entering the epithelial cell, the
fatty acids and monoglycerides are taken up by the smooth endoplasmic
reticulum, and here they are mainly recombined to form new triglycerides. However, a few of the monoglycerides are
further digested into glycerol and fatty acids by an epithelial cell lipase.
Then, the free fatty acids are
reconstituted by the smooth endoplasmic reticulum into triglycerides. Most of the glycerol that is utilized for
this purpose is synthesized de novo from alpha-glycerophosphate, this synthesis
requiring both energy from ATP and a complex of enzymes to catalyze the
reactions. Once formed, the
triglycerides aggregate within the endoplasmic reticulum into globules along with absorbed cholesterol, absorbed
phospholipids, and small amounts of newly synthesized cholesterol and
phospholipids. The phospholipids
arrange themselves in these globules with the fatty portion of the phospholipid
toward the center and the polar portions located on the surface. This
provides an electrically charged surface that makes these globules miscible
with the fluids of the cell. In addition, small amounts of lipoprotein, also
synthesized by the endoplasmic reticulum, coat part of the surface of each
globule. In this form the globule
diffuses to the side of the epithelial cell and is excreted by the process of
cellular exocytosis into the space
between the cells; from there it
passes into the lymph in the central lacteal of the villus. These globules are
then called chylomicrons.
Transport of the
Chylomicrons in the Lymph. From the sides
of the epithelial cells the chylomicrons wend their way into the central
lac-teals of the villi and from here are propelled, along with the lymph, by
the lymphatic pump upward through the thoracic duct to be emptied into the
great veins of the neck. Between 80
and 90 per cent of all fat absorbed from the gut is absorbed in this manner and
is transported to the blood by way of
the thoracic lymph in the form of chylomicrons.
Direct Absorption of fatty acids into the
portal blood. Small quantities of short
chain fatty acids, such as those from butterfat, are absorbed directly into
the portal blood rather than being converted into triglycerides and absorbed
into the lymphatics. The cause of
this difference between short and long chain fatty acid absorption is that the
shorter chain fatty acids are more water-soluble and are not reconverted into
triglycerides by the endoplasmic reticulum. This allows direct diffusion of these fatty acids from the epithelial
cells into the capillary blood of the dlood.
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Catabolism of triacylglycerols
Dietary
acylglycerols undergo hydrolysis in the small intestine by the action of
lipases, e.g., those present in pancreatic juice. Lipase digests the
triacylglycerols to 2-monoglycerols, glycerol and free fatty acids. These
components are absorbed and metabolized in the enterocytes, blood and liver. In
the enterocytes and liver the specific for organism acylglycerols are
synthesized. Then these are accumulated in
adipose tissue and in much smaller quantity in other organs.
Fermentative hydrolysis of in
adipocytes and other cells is implemented in several stages. Diacylglycerols,
monoacylglycerols, glycerol and free fatty acids are formed in this process:
OXIDATION OF FATTY ACIDS
Fatty acids
play an extremely important part as an energy-rich fuel in higher animals and
plants since large amounts can be stored in cells in the form of
triacylglycerols. Triacylglycerols are especially well adapted for this role
because they have a high energy content (about 9 kcal/g) and can be accumulated
in nearly anhydrous form as intracellular fat droplets. In contrast, glycogen
and starch can yield only about 4 kcal/g; moreover, since they are highly
hydrated, they cannot be stored in such
concentrated form. Fatty acids provide up to 40 percent of the total fuel
requirement in man on a normal diet.
http://www.youtube.com/watch?v=3xF_LK9pnL0&feature=related
Sources of Fatty Acids.
Mammalian tissues normally contain only
vanishingly small amounts of free fatty acids, which are in fact somewhat
toxic. By the action of hormonally controlled
lipases free fatty acids are formed from triacylglycerols in fat or adipose
tissue. The free fatty acids are then released from the tissue, become tightly
bound to serum albumin, and in this form are carried via the blood to other
tissues for oxidation. Fatty acids delivered in this manner are first
enzymatically "activated" in the cytoplasm and then enter the
mitochondria for oxidation.
Long-chain fatty acids are
oxidized to CO2 and H2O in nearly all tissues of
vertebrates except the brain. Some tissues, such as heart muscle, obtain most
of their energy from the oxidation of fatty acids. The mobilization,
distribution, and oxidation of fatty acids are integrated with the utilization
of carbohydrate fuels; both are under complex endocrine regulation.
The pathway of fatty acid oxidation.
Knoop
postulated that fatty acids are oxidized by b-oxidation, i.e., oxidation at the b carbon to yield a b-keto acid,
which was assumed to undergo cleavage to form acetic acid and a fatty acid
shorter by two carbon atoms.
Outline of the fatty acid oxidation
cycle.
Before
oxidation, long-chain fatty acids from the cytosol must undergo a rather
complex enzymatic activation, followed by transport across the mitochondrial
membranes into the major compartment. There the fatty acyl group is transferred
to intramitochondrial coenzyme A, yielding a fatty acyl-CoA thioester. The
subsequent oxidation of the fatty acyl-CoA takes place entirely in the
mitochondrial matrix. The fatty
acyl-CoA is dehydrogenated by removal of a pair of hydrogen atoms from the a and b carbon atoms (atoms 2 and 3) to yield the a,b-unsaturated acyl-CoA. This is then enzymatically hydrated to form a b-hydroxyacyl-CoA, which in turn is dehydrogenated in
the next step to yield the b-ketoacyl-CoA. It then undergoes enzymatic cleavage by reaction with a
second molecule of CoA. One product is acetyl-CoA, derived from carbon atoms 1
and 2 of the original fatty acid chain. The other product, a long-chain
saturated fatty acyl-CoA having two fewer carbon atoms than the original fatty
acid, now becomes the substrate for another round of reactions, beginning at
the first dehydrogenation step and ending with the removal of a second
two-carbon fragment as acetyl-CoA. At each passage through this spiral the
fatty acid chain loses a two-carbon fragment as acetyl-CoA. The 16-carbon
palmitic acid thus undergoes a total of seven such cycles, to yield altogether
8 molecules of acetyl-CoA and 14 pairs of hydrogen atoms. The palmitate must be
primed or activated only once, since at the end of each round the shortened
fatty acid appears as its CoA thioester.
The hydrogen atoms
removed during the dehydrogenation of the fatty acid enter the respiratory
chain; as electrons pass to molecular oxygen via the cytochrome system,
oxidative phosphorylation of ADP to ATP occurs. The acetyl-CoA formed as
product of the fatty acid oxidation system enters the tricarboxylic acid cycle.
Activation and entry of fatty acids into mitochondria.
There are three stages
in the entry of fatty acids into mitochondria from the extramitochondrial
cytoplasm: (1) the enzymatic ATP-driven esterification of the free fatty acid
with extramitochondrial CoA to yield fatty acyl-CoA, a step often referred to
as the activation of the fatty acid, (2) the transfer of the acyl group from
the fatty acyl-CoA to the carrier molecule carnitine, followed by the
transport of the acyl carnitine across the inner membrane, and (3) the transfer
of the acyl group from fatty acyl carnitine to intramitochondrial CoA.
Activation of fatty acids.
At least three different enzymes
catalyze formation of acyl-CoA thioesters, each being specific for a given
range of fatty acid chain length. These enzymes are called acyl-CoA
synthetases. Acetyl-CoA synthetase activates acetic, propionic, and acrylic
acids, medium-chain acyl-CoA synthetase activates fatty acids with 4 to
12 carbon atoms, and long-chain acyI-CoA synthetase activates fatty acids with
12 to 22 or more carbon atoms. The last two enzymes activate both saturated
and unsaturated fatty acids. Otherwise the properties and mechanisms of all
three synthetases, which have been isolated in highly purified form, are nearly
identical. The overall reaction catalyzed by the ATP-linked acyl-CoA
synthetases is:
RCOOH + ATP + CoA–SH Û
RCO—S—CoA + AMP + PP
Fatty
acids acyl-CoA
In this
reaction a thioester linkage is formed between the fatty acid carboxyl group
and the thiol group of CoA; the ATP undergoes pyrophosphate cleavage to yield
AMP and inorganic pyrophosphate.
The acyl-CoA synthetases are found in the outer
mitochondrial membrane and in the endoplasmic reticulum.
Transfer
to carnitine.
Long-chain saturated fatty acids have
only a limited ability to cross the inner membrane as CoA
thioesters, but their entry is greatly stimulated by carnitine.
The stimulation of fatty acid
oxidation by carnitine is due to the action of an enzyme carnitine acyltransferase, which catalyzes transfer of the fatty
acyl group from its thioester linkage with CoA to an oxygen-ester linkage with
the hydroxyl group of carnitine. The acyl carnitine ester so formed then passes
through the inner membrane into the matrix, presumably via a specific
transport system.
Carnitine Acyl-CoA
Acyl-carnitine
Transfer to
intramitochondrial CoA.
In the last stage of the entry process the acyl group
is transferred from carnitine to intramitochondrial CoA by the action of a
second type of carnitine acyltransferase
located on the inner surface of the inner membrane:
Acyl carnitine + CoA Û acyl-CoA + carnitine
This complex entry mechanism,
often called the fatty acid shuttle, has the effect of keeping the
extramitochondrial and intramitochondrial pools of CoA and of fatty acids
separated. The intramitochondrial fatty acyl-CoA now becomes the substrate of
the fatty acid oxidation system, which is situated in the inner matrix
compartment.
The first dehydrogenation step in
fatty acid oxidation.
Following
the formation of intramitochondrial acyl-CoA, all subsequent reactions of the
fatty acid oxidation cycle take place in the inner compartment. In the first
step the fatty acyl-CoA thioester undergoes enzymatic dehydrogenation by acyl-CoA dehydrogenase at the a and b carbon atoms (carbons 2 and 3) to form enoyl-CoA as
product. The double bond formed in this reaction has the trans geometrical
configuration. Recall, however, that the double bonds of the unsaturated fatty
acids of natural fats nearly always have the cis configuration.
There are four different
acyl-CoA dehydrogenases, each specific for a given range of fatty acid chain
lengths. All contain tightly bound flavin adenine dinucleotide (FAD) as
prosthetic groups. The FAD becomes reduced at the expense of the substrate, a
process that probably occurs through distinct one-electron steps.
The FADH2 of the
reduced acyl-CoA dehydrogenase cannot react directly with oxygen but donates
its electrons to the respiratory chain
via a second flavoprotein, electron-transferring flavoprotein, which in
turn passes the electrons to some carrier of the respiratory chain.
The
hydration step.
The double bond of the enoyl-CoA ester is then hydrated to form 3-hydroxyacyl-CoA by the enzyme enoyl-CoA hydratase.
The addition of water across the trans double bond is stereo-specific
and results in the formation of the L-stereoisomer of the 3-hydroxyacyl-CoA.
The
second dehydrogenation step.
In the next
step of the fatty acid oxidation cycle, the 3-hydroxyacyl-CoA is dehydrogenated
to form 3-ketoacyl-CoA) by 3-hydroxyacyl-CoA dehydrogenase. NAD+
is the specific electron acceptor. The reaction is:
This enzyme
is relatively nonspecific with respect to the length of the fatty acid chain
but is absolutely specific for the l stereoisomer.
The NADH formed in the reaction donates its electron equivalents to the NADH
dehydrogenase of the mitochondrial respiratory chain.
The cleavage step.
In the last step of the fatty
acid oxidation cycle, which is catalyzed by acetyl-CoA
acetyltransferase, more commonly
known as thiolase, the 3-ketoacyl-CoA
undergoes cleavage by interaction with a molecule of free CoA to yield the
carboxyl-terminal two-carbon fragment of the fatty acid as acetyl-CoA. The
remaining fatty acid, now shorter by two carbon atoms, appears as its coenzyme
A thioester.
This cleavage reaction, also called a
thiolysis or a thiolytic cleavage, is analogous to hydrolysis. Since the
reaction is highly exergonic, cleavage is favored. There appear to be two
(perhaps three) forms of the enzyme, each specific for different fatty acid
chain lengths.
The balance sheet.
We have described one turn of the
fatty acid oxidation cycle, in which one molecule of acetyl-CoA and two pairs
of hydrogen atoms have been removed from the starting long-chain fatty
acyl-CoA. The overall equation for one turn of the cycle, starting from
palmitoyl-CoA, is
Palmitoyl-CoA
+ CoA + FAD+ + NAD+
+ H2O ®
myristoyl-CoA + acetyl-CoA + FADH2
+ NADH2
We
can now write the equation for the seven turns of the cycle required to convert
one molecule of palmitoyl-CoA into eight molecules of acetyl-CoA:
Palmitoyl-CoA
+ 7CoA + 7FAD+ + 7NAD+ + 7H2O ®
8 acetyl-CoA +
7FADH2 + 7NADH2 + 7H+
Each molecule of FADH2 donates
a pair of electron equivalents to the respiratory chain at the level of
coenzyme Q; thus two molecules of ATP are generated during the ensuing electron
transport to oxygen. Similarly, oxidation of each molecule of NADH2
by the respiratory chain results in formation of three molecules of ATP. Hence, a total of five molecules of ATP is
formed by oxidative phosphorylation per molecule of acetyl-CoA cleaved.
The seven turns of the cycle required to
convert one molecule of palmitoyl-CoA rsults in the formation of 5 x 7 = 35
ATP.
The eight molecules of acetyl-CoA formed in the
fatty acid cycle may now enter the tricarboxylic acid cycle. The degradation of
1 molecule of acetyl-CoA in tricarboxylic acid cycle results in the formation
of 12 molecules of ATP. 8 molecules of acetyl-CoA give 96 molecules of ATP.
Thus, the total output of energy in full
cleavage of 1 molecule of palmitoyl-CoA is: 35 + 96 = 131 molecules of ATP.
Since one molecule of ATP is
in effect utilized to form palmitoyl-CoA from palmitate, the net yield of ATP
per molecule of palmitate is 130.
Oxidation of unsaturated fatty acids.
Unsaturated
fatty acids, such as oleic acid, are oxidized by the same general pathway as
saturated fatty acids, but two special problems arise. The double bonds of
naturally occurring unsaturated fatty acids are in the cis configuration,
whereas the unsaturated acyl-CoA intermediates in the oxidation of saturated
fatty acids are trans, as we have seen. Moreover, the double bonds of most
unsaturated fatty acids occur at such positions in the carbon chain that successive
removal of two-carbon fragments from the carboxyl end yields a D3-unsaturated fatty acyl-CoA rather than the D2 fatty acyl-CoA serving as the normal
intermediate in the fatty acid cycle.
These problems have been resolved
with the discovery of an auxiliary enzyme, enoyl-CoA isomerase, which
catalyzes a reversible shift of the double bond from the D3-cis to the D2-trans configuration. The
resulting D2-trans-unsaturated
fatty acyl-CoA is the normal substrate for the next enzyme of the fatty acid
oxidation sequence, enoyl-CoA hydratase,
which hydrates it to form L-3-hydroxyacyl-CoA. The complete oxidation of
oleyl-CoA to nine acetyl-CoA units by the fatty acid oxidation cycle thus requires
an extra enzymatic step catalyzed by the enoyl-CoA
isomerase, in addition to those steps required in the oxidation of
saturated fatty acids.
Polyunsaturated fatty acids, such as
linoleic acid, require a second auxiliary enzyme to complete their oxidation,
since they contain two or more cis
double bonds. When three successive acetyl-CoA units are removed from
linoleyl-CoA, a D3-cis double
bond remains, as in the case of oleyl-CoA. This is then transformed by the
enoyl-CoA isomerase described above to the D2-trans isomer. This undergoes the usual reactions,
with loss of two acetyl-CoA's, leaving an eight-carbon D2-unsaturated acid. Note,
however that the double bond of the latter is in the cis configuration.
Although the D2-cis double
bond can be hydrated by enoyl-CoA hydratase, the product is the D stereoisomer
of a 3-hydroxyacyl-CoA, not the L stereoisomer normally formed during oxidation
of saturated fatty acids. Utilization of the d
stereoisomer requires a second auxiliary enzyme, 3-hydroxyacyl-CoA
epimerase, which catalyzes epi-merization at carbon atom 3 to yield the l isomer. The product of this
reversible reaction is then oxidized by the L-specific 3-hydroxyacyl-CoA
dehydrogenase and cleaved by thiolase to complete the oxidation cycle. The remaining
six-carbon saturated fatty acyl-CoA derived from linoleic acid can now be
oxidized to three molecules of acetyl-CoA. These two auxiliary enzymes of the
fatty acid oxidation cycle make possible the complete oxidation of all the
common unsaturated fatty acids found in naturally occurring lipids. The number
of ATP molecules yielded during the complete oxidation of an unsaturated fatty
acid is somewhat lower than for the corresponding saturated fatty acid since
unsaturated fatty acids have fewer hydrogen atoms and thus fewer electrons to
be transferred via the respiratory chain to oxygen.
Oxidation of odd-carbon fatty acids and the
fate of propionyl-CoA
Odd-carbon fatty acids, which
are rare but do occur in some marine organisms, can also be oxidized in the
fatty acid oxidation cycle. Successive acetyl-CoA residues are removed until
the terminal three-carbon residue pro-pionyl-CoA is reached. This compound is
also formed in the oxidative degradation of the amino acids valine and
isoleucine. Propionyl-CoA undergoes enzymatic carboxylation in an ATP-dependent
process to form Ds-methylmaionyl-CoA, a reaction catalyzed by
propionyl-CoA corboxylase. This enzyme contains biotin as its prosthetic group.
In the next step Ds-methylmalonyl-CoA undergoes enzymatic
epimerization to LR-methylmalonyl-CoA, by action of
methyimaionyl-CoA racemase. In the next reaction step, catalyzed by methylmalonyl-CoA mutase, LR-methylmalonyl-CoA
is isomerized to succinyl-CoA, which may then undergo deacylation by reversal
of the succinyl-CoA synthetase reaction
to yield free succinate, an intermediate of the tricarboxylic acid
cycle.
Methylmalonyl-CoA mutase requires as
cofactor coenzyme B12.
Study of this intramolecular reaction with isotope tracers has revealed that
it takes place by the migration of the entire —CO—S—CoA group from carbon atom
2 of methylmalonyl-CoA to the methyl carbon atom in exchange for a hydrogen
atom.
Patients suffering from pernicious
anemia, who are deficient in vitamin B12 because of their lack of
intrinsic factor, excrete large amounts of methylmalonic acid and its precursor
propionic acid in the urine, showing that in such patients the coenzyme B12-dependent
methylmalonyl-CoA mutase reaction is defective.
OXIDATION OF GLYCEROL
Glycerol formed in cleavage of
tryacylglycerols enter catabolism or use for biosynthesis of glycerides again.
Before including of glycerol in metabolism it is activated by ATP to
glycerol-3-phosphate by action of glycerol
phosphokinase:
Glycerol Glycerol-3-phosphate
Glycerol-3-phosphate is
oxidized by glycerophosphate
dehydrogenase and glyceroaldehyde-3-phosphate is produced:
Glycerol-3-phosphate Glyceroaldehyde-3-phosphate
Glyceroaldehyde-3-phosphate is
the central metabolite of glycolysis.
The biosynthesis of lipids is a prominent
metabolic process in most organisms. Because of the limited capacity of higher
animals to store polysaccharides, glucose ingested in excess of immediate
energy needs and storage capacity is converted by glycolysis into pyruvate and
then acetyl-CoA, from which fatty acids are synthesized. These in turn are
converted into triacylglycerols, which have a much higher energy content than
polysaccharides and may be stored in very large amounts in adipose or fat
tissues. Triacylglycerols are also stored in the seeds and fruits of many
plants.
The formation of the various phospholipids and
sphingolipids of cell membranes is also an important biosynthetic process.
These complex lipids undergo continuous metabolic turnover in most cells.
Biosynthesis
of saturated fatty acids
The biosynthesis of saturated
fatty acids from their ultimate precursor acetyl-CoA occurs in all organisms
but is particularly prominent in the liver, adipose tissues, and mammary
glands of higher animals. It is brought about by a process that differs
significantly from the opposed process of fatty acid oxidation. In the first
place total biosynthesis of fatty acids occurs in the cytosol, whereas fatty
acid oxidation occurs in the mitochondria. Second, the presence of citrate is
necessary for maximal rates of synthesis of fatty acids, whereas it is not
required in fatty acid oxidation. Perhaps the most unexpected difference is
that CO2 is essential for fatty acid synthesis in cell extracts,
although isotopic CO2 is not itself incorporated into the newly
synthesized fatty acids. These and many other observations have revealed that
fatty acid synthesis from acetyl-CoA takes place with an entirely different set
of enzymes from those employed in fatty acid oxidation.
In the overall reaction of fatty acid
synthesis, which is catalyzed by a complex multienzyme system in the cytosol,
the fatty-acid synthetase complex,
acetyl-CoA derived from carbohydrate or amino acid sources is the ultimate
precursor of all the carbon atoms of the fatty acid chain. However, of the
eight acetyl units required for biosynthesis of palmitic acid, only one is
provided by acetyl-CoA; the other seven arrive in the form of malonyl-CoA,
formed from acetyl-CoA and HCO3- in a carboxylation
reaction. One acetyl residue and seven malonyl residues undergo successive
condensation steps, with release of seven molecules of CO2, to form
palmitic acid; the reducing power is furnished by NADPH:
Acetyl-CoA
+ 7 malonyl-CoA + 14NADPH + 14H+ ®
CH3(CH2)14COOH + 7CO2 + 8CoA +
14NADP+ + 6H2O
Palmitic acid
The
single molecule of acetyl-CoA required in the process serves as a primer, or
starter; the two carbon atoms of its acetyl group become the two terminal
carbon atoms (15 and 16) of the palmitic acid formed. Chain growth during fatty
acid synthesis thus starts at the carboxyl group of acetyl-CoA and proceeds by
successive addition of acetyl residues at the carboxyl end of the growing
chain. Each successive acetyl residue is derived from two of the three carbon
atoms of a malonic acid residue entering the system in the form of malonyl-CoA;
the third carbon atom of malonic acid, i.e., that of the unesterified carboxyl
group, is lost as CO2. The final product is a molecule of palmitic
acid.
A distinctive feature of the
mechanism of fatty acid biosynthesis is that the acyl intermediates in the
process of chain lengthening are thio esters, not of CoA, as in fatty acid
oxidation, but of a low-molecular-weight conjugated protein called acyl carrier protein (ACP). This protein
can form a complex or complexes with the six other enzyme proteins required for
the complete synthesis of palmitic acid. In most eukariotic cells all seven
proteins of the fatty acid synthetase complex are associated in a multienzymes
cluster.
In
most organisms the end product of the fatty-acid synthetase system is palmitic
acid, the precursor of all other higher saturated fatty acids and of all
unsaturated fatty acids.
The carbon
source for fatty acid synthesis
The ultimate source of all the carbon
atoms of fatty acids is acetyl-CoA, formed in the mitochondria by the oxidative
decarboxylation of pyruvate, the oxidative degradation of some of the amino
acids, or by the b-oxidation of long-chain fatty acids.
Acetyl-CoA itself cannot pass
out of the mitochondria into the cytosol; however, its acetyl group is
transferred through the membrane in other chemical forms. Citrate, formed in
mitochondria from acetyl-CoA and oxaloacetate, may pass through the
mitochondrial membrane to the cytoplasm via the tricarboxylate transport
system. In the cytosol acetyl-CoA is regenerated from citrate by ATP-citrate lyase, also called citrate cleavage enzyme, which catalyzes
the reaction:
Citrate + ATP + CoA ® acetyl-CoA + ADP + P + oxaloacetate
In a second pathway the acetyl
group of acetyl-CoA is enzymatically transferred to carnitine, which acts as a
carrier of fatty acids into mitochondria preparatory to their oxidation.
Acetylcarnitine passes from the mitochondrial matrix through the mitochondrial
membrane into the cytosol; acetyl-CoA is then regenerated by transfer of the
acetyl group from acetylcarnitine to cytosol CoA.
Formation of
malonyl-CoA: acetyl-CoA carboxylase
Before the acetyl groups of
acetyl-CoA can be utilized by the fatty-acid synthetase complex, an important preparatory
reaction must take place to convert acetyl-CoA into malonyl-CoA, the immediate
precursor of 14 of the 16 carbon atoms of palmitic acid. Malonyl-CoA is formed
from acetyl-CoA and bicarbonate in the cytosol by the action of acetyl-CoA carboxylase, a complex enzyme
that catalyzes the reaction:
Acetyl-CoA
Malonyl-CoA
The carbon atom of the CO2 becomes
the distal or free carboxyl carbon of malonyl-CoA. However, the above equation give
only the overall reaction, the sum of at least three intermediate reactions.
Acetyl-CoA carboxylase contains biotin as its prosthetic group. The
carboxyl group of biotin is bound in amide linkage to the e-amino group of a specific lysine residue of a subunit of the enzyme.
The covalently bound biotin serves as an intermediate carrier of a molecule of
CO2.
The
reaction catalyzed by acetyl-CoA carboxylase, an allosteric enzyme, is the
primary regulatory, or rate-limiting, step in the biosynthesis of fatty acids.
Acetyl-CoA carboxylase is virtually inactive in the absence of its positive
modulators citrate or isocitrate. The striking allosteric stimulation of this
enzyme by citrate accounts for the fact that citrate is required for fatty
acid synthesis in cell extracts without being used as a precursor.
Acetyl-CoA
carboxylase occurs in both an inactive monomeric form and an active polymeric
form. As it occurs in the avian liver, the inactive enzyme monomer has a
molecular weight of 410,000 and contains one binding site for CO2 (that
is, one biotin prosthetic group), one binding site for acetyl-CoA, and one for
citrate. Citrate shifts the equilibrium between the inactive monomer and the
active polymer, to favor the latter.
Polymeric
acetyl-CoA carboxylase of animal tissues consists of long filaments of enzyme
monomers; each monomer unit contains a molecule of bound citrate. The length of
the polymeric form varies, but on the average each filament contains about 20
monomer units, has a particle weight of some 8 megadaltons, and is about 400 nm
long. Such filaments have been studied in the electron microscope and have
actually been observed in the cytoplasm of adipose cells.
The acetyl-CoA carboxylase
reaction is complex. In fact, the monomeric unit of the enzyme contains four
different subunits. The sequence of reactions in the formation of malonyl-CoA
has been deduced from study of the four subunits of the monomer. One of these
subunits, biotin carboxylase (BC),
catalyzes the first step of the overall reaction, namely, the carboxylation of
the biotin residue covalently bound to the second subunit, which is called biotin
carboxyl-carrier protein (BCCP). The second step in the overall reaction is
catalyzed by the third type of subunit, called carboxyl transferase (CT). In these reactions the biotin residue of
the carboxyl carrier protein serves as a swinging arm to transfer the
bicarbonate ion from the biotin carboxylase subunit to the acetyl-CoA bound to
the active site of the carboxyltransferase subunit. The change from the
inactive monomeric form of acetyl-CoA carboxylase to the polymeric, active form
of the enzyme occurs when citrate is bound to the fourth subunit of each
monomeric unit.
The reactions of the fatty-acid synthetase system
http://www.youtube.com/watch?v=5HF9itMaOKo
http://www.youtube.com/watch?v=NDjffxsKd6c&feature=related
http://www.youtube.com/watch?v=kOTRNFZHmTI&feature=related
Once malonyl-CoA has been generated from acetyl-CoA
by the action of the rather complex acetyl-CoA carboxylase reaction, the
ensuing reactions of fatty acid synthesis occur in a sequence of six successive
steps catalyzed by the six enzymes of the fatty-acid synthetase system. The
seventh protein of this system, which has no enzymatic activity itself, is acyl carrier protein, to which the growing fatty acid chain is covalently attached.
Acyl carrier protein (ACP)
Acyl carrier protein,
universally symbolized as ACP, was first isolated in pure form from E. coli and
has since been studied from many other sources. The E. coli ACP is a relatively
small (mol wt 10,000), heat-stable protein containing 77 amino acid residues,
whose sequence has been established, and a covalently attached prosthetic group.
The single sulfhydryl group of
ACP, to which the acyl intermediates are esterified, is contributed by its
prosthetic group, a molecule of 4'-phosphopantetheine,
which is covalently linked to the hydroxyl group of serine residue 36 of the
protein. The 4'-phosphopantetheme moiety is identical with that of coenzyme A,
from which it is derived. The function of ACP in fatty acid synthesis is
analogous to that of CoA in fatty acid oxidation: it serves as an anchor to
which the acyl intermediates are esterified.
The priming reaction
To prime the fatty-acid
synthetase system, acetyl-CoA first reacts with the sulfhydryl group of ACP by
the action of one of the six enzymes of the synthetase system, ACP-acyltransferase, which catalyzes the
reaction:
The malonyl transfer step
In
the next reaction, catalyzed by ACP
malonyltransferase, malonyl-S-CoA formed in the acetyl-CoA carboxylase reaction
reacts with the —SH group of the 4'-phosphopantetheine arm of ACP, with loss of
free CoA, to form malonyl-S-ACP:
Malonyl—S—CoA
+ ACP—SH Û malonyl—S—ACP + CoA—SH
As a result of this step and of the
preceding priming reaction, a malonyl group is now esterified to ACP and an
acetyl group is esterified to an —SH group on the ACP molecule.
The condensation reaction
In the next reaction of the
sequence, catalyzed by b-ketoacyl-ACP synthase, the acetyl group esterified to the cysteine residue is transferred to
carbon atom 2 of the malonyl group on ACP, with release of the free carboxyl
group of the malonyl residue as CO2:
Study of the reaction equilibrium has revealed
the probable basis for the biological selection of malonyl-CoA as the
precursor of two-carbon residues for fatty acid synthesis. If acetoacetyl-CoA
were to be formed from two molecules of acetyl-CoA by the action of acetyl-CoA
acetyltransferase,
Acetyl—S—CoA + acetyl—S—CoA Û
acetoacetyl—S—CoA + CoA—SH
the
reaction would be endergonic, with its equilibrium lying to the left.
The first reduction reaction
The acetoacetyl-S-ACP
now undergoes reduction by NADPH to form b-hydroxybutyryl-S-ACP. This reaction is catalyzed by b-ketoacyl-ACP
reductase:
The dehydration step
b-Hydroxybutyryl-S-ACP is next dehydrated to the
corresponding unsaturated acyl-S-ACP, namely, crotonyl-S-ACP, by b-hydroxyacyl—ACP-dehydratase:
The second reduction step
Crotonyl-S-ACP is now
reduced to butyryl-S-ACP by enoil-ACP reductase (NADPH); the electron donor is NADPH in animal tissues:
Crotonyl-S-ACP Butyryl-S-ACP
This reaction also differs
from the corresponding reaction of fatty acid oxidation in mitochondria in that
a pyridine nucleotide rather than a flavoprotein is involved. Since the
NADPH-NADP+ couple has a more negative standard potential than the
fatty acid oxidizing flavoprotein, NADPH favors reductive formation of the saturated
fatty acid.
The formation of butyryl-ACP completes the first of seven
cycles en route to palmitoyl-S-ACP.
To start the next cycle the butyryl group is transferred from —SH group of
phosphopantetheine to the —SH group of cysteine, thus allowing —SH group of ACP
phosphopantetheine to accept a malonyl group from another molecule of malonyl-CoA.
Then the cycle repeats, the next step
being the condensation of malonyl-S-ACP with butyryl-S-ACP to yield b-ketohexanoyl-S-ACP and CO2.
After seven complete cycles, palmitoyl-ACP is the end product. The
palmitoyl group may be removed to yield free palmitic acid by the action of a thioesterase, or it may be transferred
from ACP to CoA, or it may be incorporated directly into phosphatidic acid in
the pathway to phospholipids and triacylglycerols.
It
is remarkable that in most organisms the fatty-acid synthetase system stops
with the production of palmitic acid and does not yield stearic acid, which has
only two more carbon atoms than palmitic acid and thus does not differ greatly
in physical properties.
Saturated fatty acids having an odd
number of carbon atoms, which are found in many marine organisms, are also made
by the fatty-acid synthetase complex. In this case the synthesis is primed by a
starter molecule of propionyl-S-ACP (instead of acetyl-S-ACP), to which are
added successive two-carbon units via condensations with malonyl-S-ACP.
We
can now write the overall equation for palmitic acid biosynthesis starting from
acetyl-S-CoA:
8 Acetyl—S—CoA + 14NADPH
+ 14H+ + 7ATP + H2O ®
palmitic acid + 8CoA + 14NADP+ + 7ADP + 7P.
The 14 molecules of NADPH
required for the reductive steps in the synthesis of palmitic acid arise
largely from the NADP-dependent oxidation of
glucose 6-phosphate via the phosphogluconate
pathway. Liver, mammary gland, and adipose tissue of vertebrates, which have a
rather high rate of fatty acid biosynthesis, also have a very active
6-phosphogluconate pathway.
The
enzymatic steps leading to the biosynthesis of palmitic acid differ from those
involved in oxidation of palmitic acid in the following respects:
1. Their intracellular
location.
2. The type of acyl-group
carrier.
3. The form in which the
two-carbon units are added or removed.
4. The pyridine nucleotide
specificity of the b-ketoacyl-b-hydroxyacyl reaction.
5. The stereoisomeric configuration
of the b-hydroxyacyl intermediate.
6. The electron donor-acceptor
system for the crotonyl-butyryl step.
These differences illustrate how two
opposing metabolic processes may proceed independently of each other in the
cell.
Elongation of saturated fatty
acids in mitochondria and microsomes
Palmitic acid, the normal end product of the
fatty-acid synthetase system, is the precursor of the other long-chain saturated
and unsaturated fatty acids in most organisms. Elongation of palmitic acid to
longer-chain saturated fatty acids, of which stearic acid is most abundant, occurs by the action of two
different types of enzyme systems, one in the mitochondria and the other in the
endoplasmic reticulum.
In mitochondria palmitic and other
saturated fatty acids are lengthened by successive additions to the
carboxyl-terminal end of acetyl units in the form of acetyl-CoA; malonyl-ACP
cannot replace acetyl-CoA. The mitochondrial elongation pathway occurs by
reactions similar to those in fatty acid oxidation. Condensation of
palmityl-CoA with acetyl-CoA yields b-ketostearyl-CoA, which is reduced by NADPH to b-hydroxystearyl-CoA. The latter is dehydrated to the
unsaturated stearyl-CoA, which is then reduced to yield stearyl-CoA at the
expense of NADPH. This system will also elongate unsaturated fatty acids.
Microsome
preparations can elongate both saturated and unsaturated fatty acyl-CoA esters,
but in this case malonyl-CoA rather than acetyl-CoA serves as source of the
acetyl groups. The reaction sequence is identical to that in the fatty-acid
synthetase system except that the microsomal system employs CoA and not ACP as
acyl carrier.
Formation
of monoenoic acids
Palmitic and
stearic acids serve as precursors of the two common monoenoic (monounsaturated) fatty acids of animal tissues, namely, poimitoleic and oleic acids, both of which possess a cis double bond in the D9 position. Although most organisms can form
palmitoleic and oleic acids, the pathway and enzymes employed differ between
aerobic and anaerobic organisms. In
vertebrates (and most other aerobic organisms) the D9 double
bond is introduced by a specific monooxygenase system; it is located in the
endoplasmic reticulum of liver and adipose tissue. One molecule of molecular
oxygen (O2) is used as the acceptor for two pairs of electrons, one
pair derived from the palmitoyl-CoA or stearyl-CoA substrate and the other from
NADPH, which is a required coreductant in the reaction. The transfer of electrons
in this complex reaction involves a microsomal electron-transport chain which
carries electrons from NADPH (or NADH) to microsomal cytochrome b5 via cytochrome
b5 reductase, a
flavoprotein. A terminal cyanide-sensitive factor (CSF), a protein, is required
to activate the acyl-CoA and the oxygen.
The overall reaction for
palmitoyl-CoA is:
Palmitoyl—CoA + NADPH + H+ + O2 ® palmitoleyl—CoA + NADP+ + 2H2O.
Formation
of polyenoic acids
Bacteria do not contain
polyenoic acids; however, these acids are abundant both in higher plants and in
animals. Mammals contain four distinct families of polyenoic acids, which differ
in the number of carbon atoms between the terminal methyl group and the
nearest double bond. These families are named from their precursor fatty
acids, namely, palmitoleic, oleic,
linoleic, and linolenic acids. All polyenoic acids found in mammals are
formed from these four precursors by further elongation and/or desaturation
reactions. Two of these precursor fatty acids, linoleic and linolenic acids,
cannot be synthesized by mammals and must be obtained from plant sources; they
are therefore called essential fatty
acids.
The elongation of chains of polyenoic
acids occurs at the carboxyl end by the mitochondrial or microsomal systems
described above. The desaturation steps occur by the action of the cytochrome b5-oxygenase
system with NADPH as coreductant of oxygen, like the steps in the formation of
palmitoleic and oleic acids, also described above.
Arachidonic acid is the most abundant polyenoic acid. When young rats are placed on
diets deficient in essential fatty acids, they grow slowly and develop a scaly
dermatitis and thickening of the skin. This condition can be relieved by
administration not only of linoleic or linolenic acid but also of arachidonic
acid. The essential fatty acids and some of their derivatives serve as precursors of the prostaglandins.
In
plants linoleic and linolenic acids are synthesized from oleic acid via aerobic
desaturation reactions catalyzed by specific oxygenase systems requiring NADPH
as coreductant.
The
double bonds of naturally occurring fatty acids do not in general undergo
hydrogenation to yield more completely saturated fatty acids; only a few
organisms appear to carry out this process. Unsaturated fatty acids, however,
are completely oxidized by the fatty acid oxidation system.
In
most organisms the conversion of saturated to unsaturated fatty acids is
promoted by low environmental temperatures. This is an adaptation to maintain
the melting point of the total cell lipids below the ambient temperature;
unsatu-rated fatty acids have lower melting points than saturated. In some
organisms the enzymes involved in fatty acid desaturation increase in
concentration in response to low temperatures; in others the unsaturated fatty
acids are inserted into lipids at increased rates.
Biosynthesis of triacylglycerols
The triacylglycerols, which function as depot, or storage, lipids, are
actively synthesized in the cells of vertebrates, particularly liver and fat
cells, as well as those of higher plants. Bacteria in general contain
relatively small amounts of triacyglycerols.
In higher animals and plants two
major precursors are required for the synthesis of triacylglycerols: L-glycerol 3-phosphate and fatty acyl-CoA.. L-Glycerol 3-phosphate is derived from two different sources. Its
normal precursor is dihydroxyacetone phosphate,
the product of the aldolase reaction
of glycolysis. Dihydroxyacetone phosphate is reduced to L-glycerol 3-phosphate
by the NAD-linked glycerol- 3-phosphate
dehydrogenase of the cytosol:
Dihydroxyacetone phosphate + NADH + H+
® L-glycerol 3-phosphate + NAD+
It may also be formed from free glycerol
arising from degradation of triacylglycerols, through the action of glycerol kinase:
ATP + glycerol ® L-glycerol 3-phosphate + ADP
The first stage in
triacyglycerol formation is the acylation of the free hydroxyl groups of
glycerol phosphate by two molecules of fatty acyl-CoA to yield first a lysophosphotidic acid and then a phosphatidic acid:
Glycerol
phosphate Lysophosphotidic
acid 
Lysophosphotidic acid
Phosphatidic acid
Free glycerol is not
acylated. These reactions occur preferentially with 16- and 18-carbon saturated
and unsaturated acyl-CoA.
Phosphatidic
acids occur only in trace amounts in cells, but they are important
intermediates in the biosynthesis of triacylglycerols and phosphoglycerides.
In the pathway to
triacylglycerols, phosphatidic acid undergoes hydrolysis by phosphatidate phosphatase to form a diacylglycerol:
Phosphatidic acid Diacylglycerol
The diacylglycerol then reacts with a
third molecule of a fatty acyl-CoA to yield a triacylglycerol by the action of diacylglycerol acyltransferase:
Diacylglycerol Triacylglycerol
In the intestinal mucosa of higher
animals, which actively synthesizes triacylglycerols during absorption of fatty
acids from the intestine, another type of acylation reaction comes into play.
Monoacylglycerols formed during intestinal digestion may be acylated directly
by acylglycerol palmitoyltrans-ferase
and thus phosphatidic acid is not an intermediate:
Monoacylglycerol + palmitoyl-CoA ® diacylglycerol + CoA
In
storage fats of animal and plant tissues the triacylglycerols are usually
mixed, i.e., contain two or more different fatty acids.
PROTEIN CATABOLISM – hydrolysis breaks peptide bonds
yielding amino acids
http://www.youtube.com/watch?v=SkkoE1RN_5E
AMINO ACID CATABOLISM - (requires B6)
PROTEIN
CATABOLISM – attaches an amino group of an amino acid to a keto
acid converting a keto acid
into an amino acid. The original amino acid becomes a
keto acid.
1. New amino acid can be used for synthesis
2. Keto acid can be broken down in the TCA cycle
DEAMINATION – uses deaminase, water & NAD
1. breaks down an amino acid into a keto acid
and an ammonia.
2. liver cells convert ammonia to urea via the
PROTEIN ANABOLISM – dehydration synthesis
A. Amination – attaches amino group to a keto
acid
B. Ten essential amino acids
C. Deficiency diseases
1. marasmus
2. kwashiorkor
D. Genetic metabolic disorder - PKU
Breakdown of Food and Fat
http://www.youtube.com/watch?v=AEsQxzeAry8
The digestive process breaks down food by
chemical and mechanical action into substances that can pass into the
bloodstream and be processed by body cells.
http://www.youtube.com/watch?v=g9G0zzdQx-M&feature=related
Certain nutrients, such as salts and
minerals, can be absorbed directly into the circulation. Fat, complex
carbohydrates, and proteins are broken down into smaller molecules before being
absorbed.
Fat is split into glycerol and fatty
acids; carbohydrates are split into monosaccharide sugars; and proteins are
split into linked amino acids called peptides, and then into individual amino
acids.
http://www.youtube.com/watch?v=STzOiRqzzL4
http://www.youtube.com/watch?v=tNdBdodTJNs&feature=related
http://www.youtube.com/watch?v=NewpaNwevFk
1: Mouth and oesophagus
Food is chewed with the teeth and mixed
with saliva. The enzyme amylase, present in saliva, begins the breakdown of
starch into sugar. Each lump of soft food, called a bolus, is swallowed and
propelled by contractions down the oesophagus into the stomach.
2: Stomach
Pepsin is an enzyme produced when
pepsinogen, a substance secreted by the stomach lining, is modified by
hydrochloric acid (also produced by the stomach lining).
http://www.youtube.com/watch?v=1jtYH3RihcA
Pepsin breaks proteins down into smaller
units, called polypeptides and peptides. Lipase is a stomach enzyme that breaks
down fat into glycerol and fatty acids. The acid produced by the stomach also
kills bacteria.
3: Duodenum
Lipase, a pancreatic enzyme, breaks down
fat into glycerol and fatty acids. Amylase, another enzyme produced by the
pancreas, breaks down starch into maltose, a disaccharide sugar. Trypsin and
chymotrypsin are powerful pancreatic enzymes that split proteins into
polypeptides and peptides.
4: Small Intestine
Maltase, sucrase, and lactase are enzymes
produced by the lining of the small intestine. They convert disaccharide sugars
into monosaccharide sugars. Peptidase, another enzyme produced in the
intestine, splits large peptides into smaller peptides and then into amino
acids.
5: Large Intestine
Undigested food enters the large
intestine, where water and salt are absorbed by the intestinal lining. The
residue, together with waste pigments, dead cells , and bacteria, is pressed
into faeces and stored for excretion.
Urea Cycle
http://www.youtube.com/watch?v=AoBbVu5rnMs
Introduction
Humans are totally
dependent on other organisms for converting atmospheric nitrogen into forms
available to the body. Nitrogen fixation is carried out by bacterial
nitrogensases forming reduced nitrogen, NH4+ which can
then be used by all organisms to form amino acids.
Overview of the flow of nitrogen in the biosphere.
Nitrogen, nitrites and nitrates are acted upon by bacteria (nitrogen fixation)
and plants and we assimilate these compounds as protein in our diets. Ammonia
incorporation in animals occurs through the actions of glutamate dehydrogenase
and glutamine synthase. Glutamate plays the central role in mammalian nitrogen
flow, serving as both a nitrogen donor and nitrogen acceptor.
Reduced nitrogen enters the human body as dietary free amino acids,
protein, and the ammonia produced by intestinal tract bacteria. A pair of
principal enzymes, glutamate dehydrogenase and glutamine synthatase, are found
in all organisms and effect the conversion of ammonia into the amino acids glutamate
and glutamine, respectively. Amino and amide groups from these 2
substances are freely transferred to other carbon skeletons by transamination
and transamidation reactions.
Representative aminotransferase catalyzed reaction.
Aminotransferases exist for all amino acids except threonine and lysine.
The most common compounds involved as a donor/acceptor pair in transamination
reactions are glutamate and -ketoglutarate (-KG),
which participate in reactions with many different aminotransferases. Serum
aminotransferases such as serum glutamate-oxaloacetate-aminotransferase
(SGOT) (also called aspartate aminotransferase, AST) and serum
glutamate-pyruvate aminotransferase (SGPT) (also called alanine
transaminase, ALT) have been used as clinical markers of tissue damage,
with increasing serum levels indicating an increased extent of damage. Alanine
transaminase has an important function in the delivery of skeletal
muscle carbon and nitrogen (in the form of alanine) to the liver. In skeletal
muscle, pyruvate is transaminated to alanine, thus affording an additional
route of nitrogen transport from muscle to liver. In the liver alanine
transaminase tranfers the ammonia to -KG and regenerates pyruvate. The pyruvate can then be
diverted into gluconeogenesis. This process is refered to as the glucose-alanine cycle.
The Glutamate Dehydrogenase Reaction
The reaction catalyzed by glutamate dehydrogenase is:
NH4++-ketoglutarate+NAD(P)H+H+<---->glutamate+NAD(P)++H2O
Glutamate dehydrogenase can utilize either NAD orNADP
as cofactor. In the forward reaction as shown above glutamate
dehydrogenase is important in converting free ammonia and -ketoglutarate (-KG) to glutamate, forming one
of the 20 amino acids required for protein synthesis. However, it should be
recognized that the reverse reaction is a key anapleurotic process linking
amino acid metabolism with TCA cycle activity.In the reverse
reaction, glutamate dehydrogenase provides an oxidizable carbon
source used for the production of energy as well as a reduced electron carrier,
NADH. As expected for a branch point enzyme with an important link to energy
metabolism, glutamate dehydrogenase is regulated by the cell
energy charge. ATP and GTP are positive allosteric effectors of the formation
of glutamate, whereas ADP and GDP are positive allosteric effectors of the
reverse reaction. Thus, when the level of ATP is high, conversion of glutamate
to -KG and other TCA cycle
intermediates is limited; when the cellular energy charge is low, glutamate is
converted to ammonia and oxidizable TCA cycle intermediates. Glutamate is also
a principal amino donor to other amino acids in subsequent transamination
reactions. The multiple roles of glutamate in nitrogen balance make it a
gateway between free ammonia and the amino groups of most amino acids.
The Glutamine Synthase Reaction
The reaction
catalyzed by glutamine synthase is:
glutamate +
NH4+ + ATP -------> glutamine + ADP + Pi +
H+
The glutamine
synthatase reaction is also important in several respects. First it
produces glutamine, one of the 20 major amino acids. Second, in animals, glutamine
is the major amino acid found in the circulatory system. Its role there is to
carry ammonia to and from various tissues but principally from peripheral
tissues to the kidney, where the amide nitrogen is hydrolyzed by the enzyme glutaminase
(reaction below); this process regenerates glutamate and free ammonium ion,
which is excreted in the urine.
glutamine + H2O -------> glutamate + NH3
Note that, in this function, ammonia arising in
peripheral tissue is carried in a nonionizable form which has none of the
neurotoxic or alkalosis-generating properties of free ammonia.
Liver
contains both glutamine synthetase and glutaminase
but the enzymes are localized in different cellular segments. This ensures that
the liver is neither a net producer nor consumer of glutamine. The differences
in cellular location of these two enzymes allows the liver to scavange ammonia
that has not been incorporated into urea. The enzymes of the urea cycle are
located in the same cells as those that contain glutaminase. The result
of the differential distribution of these two hepatic enzymes makes it possible
to control ammonia incorporation into either urea or glutamine, the latter
leads to excretion of ammonia by the kidney.
When acidosis occurs the body will divert more glutamine from the liver to the
kidney. This allows for the conservation of bicarbonate ion since the
incorporation of ammonia into urea requires bicarbonate (see below). When
glutamine enters the kidney, glutaminase releases one mole of
ammonia generating glutamate and then glutamate dehydrogenase
releases another mole of ammonia generating a-ketoglutarate. The ammonia will
ionizes to ammonium ion ( NH4+) which is excreted. The
net effect is a reduction in the pH (see also Kidneys and
Acid-Base Balance).
While glutamine, glutamate, and the remaining nonessential amino acids can be
made by animals, the majority of the amino acids found in human tissues
necessarily come from dietary sources (about 400g of protein per day). Protein
digestion begins in the stomach, where a proenzyme called pepsinogen
is secreted, autocatalytically converted to Pepsin A, and used
for the first step of proteolysis. However, most proteolysis takes place in the
duodenum as a consequence of enzyme activities secreted by the pancreas. All of
the serine proteases and the zinc peptidases of pancreatic secretions are
produced in the form of their respective proenzymes. These proteases are both
endopeptidase and exopeptidase, and their combined action in the intestine
leads to the production of amino acids, dipeptides, and tripeptides, all of
which are taken up by enterocytes of the mucosal wall.
A circuitous regulatory pathway leading to the secretion of proenzymes into the
intestine is triggered by the appearance of food in the intestinal lumen.
Special mucosal endocrine cells secret the peptide hormones cholecystokinin
(CCK) and secretin into the circulatory system. Together, CCK and secretin
cause contraction of the gall bladder and the exocrine secretion of a
bicarbonate-rich, alkaline fluid, containing protease proenzymes from the
pancreas into the intestine. A second, paracrine role of CCK is to stimulate
adjacent intestinal cells to secrete enteropeptidase, a protease
that cleaves trypsinogen to produce trypsin. Trypsin
also activates trypsinogen as well as all the other proenzymes in
the pancreatic secretion, producing the active proteases and peptidases that
hydrolyze dietary polypeptides.
Subsequent to luminal hydrolysis, small peptides and amino acids are
transferred through enterocytes to the portal circulation by diffusion,
facilitated diffusion, or active transport. A number of Na+-dependent
amino acid transport systems with overlapping amino acid specificity have been
described. In these transport systems, Na+ and amino acids at high
luminal concentrations are co-transported down their concentration gradient to
the interior of the cell. The ATP-dependent Na+/K+ pump
exchanges the accumulated Na+ for extracellular K+,
reducing intracellular Na+ levels and maintaining the high
extracellular Na+ concentration (high in the intestinal lumen, low
in enterocytes) required to drive this transport process.
Transport mechanisms of this nature are ubiquitous in the body. Small peptides
are accumulated by a proton (H+) driven transport process and
hydrolyzed by intracellular peptidases. Amino acids in the circulatory system
and in extracellular fluids are transported into cells of the body by at least
7 different ATP-requiring active transport systems with overlapping amino acid
specificities.
Hartnup disorder is an autosomal recessive impairment of neutral amino
acid transport affecting the kidney tubules and small intestine. It is believed
that the defect lies in a specific system responsible for neutral amino acid
transport across the brush-border membrane of renal and intestinal epithelium.
The exact defect has not yet been characterized. The characteristic diagnostic
feature of Hartnup disorder is a dramatic neutral hyperaminoaciduria.
Additionally, individuals excrete indolic compounds that originate from the
bacterial degradation of unabsorbed tryptophan. The reduced intestinal
absorption and increased renal loss of tryptophan lead to a reduced
availability of tryptophan for niacin and nicotinamide nucleotide biosynthesis.
As a consequence affected individuals frequently exhibit pellegra-like rashes.
.
Many other
nitrogenous compounds are found in the intestine. Most are bacterial products
of protein degradation. Some have powerful pharmacological (vasopressor)
effects.
|
Products of Intestinal Bacterial Activity |
||
|
Substrates |
Products |
|
|
- |
Vasopressor
Amines |
Other |
|
Lysine |
Cadaverene |
- |
|
Arginine |
Agmatine |
- |
|
Tyrosine |
Tyramine |
- |
|
Ornithine |
Putrescine |
- |
|
Histidine |
Histamine |
- |
|
Tryptophan |
- |
Indole and
skatole |
|
All amino
acids |
- |
NH4+ |
Prokaryotes
such as E. coli can make the carbon skeletons of all 20 amino acids and
transaminate those carbon skeletons with nitrogen from glutamine or glutamate to
complete the amino acid structures. Humans cannot synthesize the branched
carbon chains found in branched chain amino acids or the ring systems found in
phenylalanine and the aromatic amino acids; nor can we incorporate sulfur into
covalently bonded structures. Therefore, the 10 so-called essential amino acids
must be supplied from the diet. Nevertheless, it should be recognized
that,depending on the composition of the diet and physiological state of an
individual,one or another of the non-essential amino acids may also become a
required dietary component. For example, arginine is not usually considered to
be essential, because enough for adult needs is made by the urea cycle.
However, the
urea cycle generally does not provide sufficient arginine for the needs of a
growing child.
To take a different type of example, cysteine and
tyrosine are considered non-essential but are formed from the essential amino
acids methionine and phenylalanine, respectively. If sufficient cysteine and
tyrosine are present in the diet, the requirements for methionine and
phenylalanine are markedly reduced; conversely, if methionine and phenylalanine
are present in only limited quantities, cysteine and tyrosine can become
essential dietary components. Finally, it should be recognized that if the -keto acids corresponding to the carbon skeleton of
the essential amino acids are supplied in the diet, aminotransferases in the
body will convert the keto acids to their respective amino acids, largely
supplying the basic needs.
Unlike fats and carbohydrates, nitrogen has no designated storage depots in the
body. Since the half-life of many proteins is short (on the order of hours),
insufficient dietary quantities of even one amino acid can quickly limit the
synthesis and lower the body levels of many essential proteins. The result of
limited synthesis and normal rates of protein degradation is that the balance
of nitrogen intake and nitrogen excretion is rapidly and significantly altered.
Normal, healthy adults are generally in nitrogen balance, with intake and
excretion being very well matched. Young growing children, adults recovering
from major illness, and pregnant women are often in positive nitrogen balance.
Their intake of nitrogen exceeds their loss as net protein synthesis proceeds.
When more nitrogen is excreted than is incorporated into the body, an
individual is in negative nitrogen balance. Insufficient quantities of even one
essential amino acid is adequate to turn an otherwise normal individual into
one with a negative nitrogen balance. The biological value of dietary proteins
is related to the extent to which they provide all the necessary amino acids.
Proteins of animal origin generally have a high biological value; plant
proteins have a wide range of values from almost none to quite high. In
general, plant proteins are deficient in lysine, methionine, and tryptophan and
are much less concentrated and less digestible than animal proteins. The
absence of lysine in low-grade cereal proteins, used as a dietary mainstay in
many underdeveloped countries, leads to an inability to synthesize protein
(because of missing essential amino acids) and ultimately to a syndrome known
as kwashiorkor, common among children in these countries.
Essential vs. Nonessential Amino Acids
|
Nonessential |
Essential |
|
Alanine |
Arginine* |
|
Asparagine |
Histidine |
|
Aspartate |
Isoleucine |
|
Cysteine |
Leucine |
|
Glutamate |
Lysine |
|
Glutamine |
Methionine* |
|
Glycine |
Phenylalanine* |
|
Proline |
Threonine |
|
Serine |
Tryptophan |
|
Tyrosine |
Valine |
|
The amino acids arginine, methionine and
phenylalanine are considered essential for reasons not directly related to
lack of synthesis. Arginine is synthesized by mammalian cells but at a rate
that is insufficient to meet the growth needs of the body and the majority
that is synthesized is cleaved to form urea. Methionine is required in large
amounts to produce cysteine if the latter amino acid is not adequately
supplied in the diet. Similarly, phenyalanine is needed in large amounts to form
tyrosine if the latter is not adequately supplied in the diet. |
|
Removal of Nitrogen
from Amino Acids
http://www.youtube.com/watch?v=5pBNunRmJn4
Nitrogen elimination begins intracellularly with
protein degradation. There are two main routes for converting intracellular
proteins to free amino acids: a lysosomal pathway, by which extracellular and
some intracellular proteins are degraded, and cytosolic pathways that are
important in degrading proteins of intracellular origin. In one cytosolic
pathway a protein known as ubiquitin is activated by conversion to an AMP derivative, and
cytosolic proteins that are damaged or otherwise destined for degradation are
enzymically tagged with the activated ubiquitin. Ubiquitin-tagged proteins are
then attacked by cytosolic ATP-dependent proteases that hydrolyze the targeted
protein, releasing the ubiquitin for further rounds of protein targeting.
The dominant reactions involved in removing amino acid nitrogen from the
body are known as transaminations. This class of reactions funnels nitrogen
from all free amino acids into a small number of compounds; then, either they
are oxidatively deaminated, producing ammonia, or their amine groups are
converted to urea by the urea cycle. Transaminations involve moving an -amino group from a donor a-amino acid to the keto
carbon of an acceptor -keto acid. These reversible reactions are catalyzed by
a group of intracellular enzymes known as aminotransferases
(transaminases), which employ covalently bound pyridoxal phosphate as a
cofactor (see reaction
mechanism).
Aminotransferases exist for all amino acids except
threonine and lysine. The most common compounds involved as a donor/acceptor
pair in transamination reactions are glutamic acid and -ketoglutaric acid, which participate in reactions
with many different aminotransferases. Serum aminotransferases such as serum
glutamate - oxaloacetate - aminotransferase (SGOT) have been used as
clinical markers of tissue damage, with increasing serum levels indicating an
increased extent of damage.
A small but clinically
important amount of creatinine is excreted in the urine daily, and the creatinine
clearance rate is often used as an indicator of kidney function. The first
reaction in creatinine formation is the transfer of the amido (or amidine)
group of arginine to glycine, forming guanidinoacetate. Subsequently, a methyl
group is transferred from the ubiquitous 1-carbon-donor S-adenosylmethionine to
guanidinoacetate to produce creatine (from which phosphocreatine is formed),
some of which spontaneously cyclizes to creatinine, and is eliminated in the
urine. The quantity of urine creatinine is generally constant for an individual
and approximately proportional to muscle mass. In individuals with damaged
muscle cells, creatine leaks out of the damaged tissue and is rapidly cyclized,
greatly increasing the quantity of circulating and urinary creatinine.
Because of the participation of -ketoglutarate in numerous transaminations, glutamate
is a prominent intermediate in nitrogen elimination as well as in anabolic
pathways. Glutamate formed in the course of nitrogen elimination is either
oxidatively deaminated by liver glutamate dehydrogenase, forming
ammonia, or converted to glutamine by glutamine synthase and
transported to kidney tubule cells. There the glutamine is sequentially
deamidated by glutaminase and deaminated by kidney glutamate
dehydrogenase.
The ammonia produced in the latter two reactions is
excreted as NH4+ in the urine, where it helps maintain
urine pH in the normal range of pH 4 to pH 8. The extensive production of
ammonia by peripheral or liver glutamate dehydrogenase is not
feasible because of the highly toxic effects of circulating ammonia. Normal serum
ammonium concentrations are in the range of 20-40 mmol, and an increase in
circulating ammonia to about 400 mmol causes alkalosis and neurotoxicity.
A final, therapeutically useful amino acid-related reaction is the amidation of
aspartic acid to produce asparagine. The enzyme asparagine synthase
catalyzes the ATP, requiring the transamidation reaction shown below:
aspartate+glutamine+ATP-------->glutamate+asparagine+AMP+PPi
Most cells perform this reaction
well enough to produce all the asparagine they need. However, some leukemia
cells require exogenous asparagine, which they obtain from the plasma.
Chemotherapy using the enzyme asparaginase takes advantage of
this property of leukemic cells by hydrolyzing serum asparagine to ammonia and
aspartic acid, thus depriving the neoplastic cells of the asparagine that is
essential for their characteristic rapid growth.
In the peroxisomes of mammalian tissues, especially liver, there are 2
stereospecific amino acid oxidases involved in elimination of
amino acid nitrogen. D-amino acid oxidase is an FAD-linked
enzyme, and while there are few D-amino acids that enter the human body the
activity of this enzyme in liver is quite high. L-amino acid oxidase
is FMN-linked and has broad specificity for the L amino acids.A number of
substances, including oxygen, can act as electron acceptors from the
flavoproteins. If oxygen is the acceptor the product is hydrogen peroxide,
which is then rapidly degraded by the catalases found in liver
and other tissues. Missing or defective biogenesis of peroxisomes or L-amino acid
oxidase causes generalized hyper-aminoacidemia and hyper-aminoaciduria,
generally leading to neurotoxicity and early death.
Amino Acid Biosynthesis
http://www.youtube.com/watch?v=VXZuuo3DD4s
Glutamate and
Aspartate
Glutamate and aspartate are synthesized from their widely distributed -keto acid precursors by simple 1-step transamination
reactions. The former catalyzed by glutamate dehydrogenase and the latter by aspartate aminotransferase,
AST.Aspartate is also derived from asparagine through the action
of asparaginase. The importance of glutamate as a common intracellular
amino donor for transamination reactions and of aspartate as a precursor of
ornithine for the urea cycle is described in the Nitrogen Metabolism page.
Alanine and the Glucose-Alanine Cycle
Aside from
its role in protein synthesis, alanine is second only to glutamine in
prominence as a circulating amino acid. In this capacity it serves a unique
role in the transfer of nitrogen from peripheral tissue to the liver. Alanine
is transferred to the circulation by many tissues, but mainly by muscle, in
which alanine is formed from pyruvate at a rate proportional to intracellular
pyruvate levels. Liver accumulates plasma alanine, reverses the transamination
that occurs in muscle, and proportionately increases urea production. The
pyruvate is either oxidized or converted to glucose via gluconeogenesis. When alanine transfer from muscle to liver is
coupled with glucose transport from liver back to muscle, the process is known
as the glucose-alanine cycle. The key feature of the cycle is that in 1 molecule,
alanine, peripheral tissue exports pyruvate and ammonia (which are potentially
rate-limiting for metabolism) to the liver, where the carbon skeleton is
recycled and most nitrogen eliminated.There are 2 main pathways to production
of muscle alanine: directly from protein degradation, and via the
transamination of pyruvate by glutamate-pyruvate aminotransferase
(also called alanine transaminase, ALT).
glutamate + pyruvate <-------> -KG + alanine
The
sulfur for cysteine synthesis comes from the essential amino acid methionine. A
condensation of ATP and methionine catalyzed by methionine
adenosyltransferase yields S-adenosylmethionine (SAM or AdoMet).
Biosynthesis of S-adenosylmethionine, SAM
SAM serves as
a precurosor for numerous methyl transfer reactions (e.g. the conversion of
norepinephrine to epinenephrine, see Specialized
Products of Amino Acids). The
result of methyl transfer is the conversion of SAM to S-adenosylhomocysteine.
S-adenosylhomocysteine is then cleaved by adenosylhomocyteinase to yield
homocysteine and adenosine. Homocysteine can be converted back to methionine by
methionine synthase, a reaction that occurs under methionine-sparing
conditions and requires N5-methyl-tetrahydrofolate as methyl donor.
This reaction was discussed in the context of vitamin B12-requiring
enzymes in the Vitamins page. Transmethylation reactions employing SAM are
extremely important, but in this case the role of S-adenosylmethionine in
transmethylation is secondary to the production of homocysteine (essentially a
by-product of transmethylase activity). In the production of SAM all
phosphates of an ATP are lost: one as Pi and two as PPi.
It is adenosine which is transferred to methionine and not AMP. In cysteine
synthesis, homocysteine condenses with serine to produce cystathionine, which
is subsequently cleaved by cystathionase to produce cysteine and -ketobutyrate. The sum of the latter two reactions is
known as trans-sulfuration. Cysteine is used for protein synthesis and
other body needs, while the ketobutyrate is decarboxylated and converted to
propionyl-CoA. While cysteine readily oxidizes in air to form the disulfide
cystine, cells contain little if any free cystine because the ubiquitous
reducing agent, glutathione effectively reverses the formation of
cystine by a non-enzymatic reduction reaction.
Utilization of methionine in the synthesis of cysteine
The 2 key
enzymes of this pathway, cystathionine synthase and cystathionase
(cystathionine lyase), both use pyridoxal phosphate as a cofactor, and both
are under regulatory control. Cystathionase is under negative allosteric
control by cysteine, as well, cysteine inhibits the expression of the cystathionine
synthase gene. Genetic defects are known for both the synthase and the lyase.
Missing or impaired cystathionine synthase leads to homocystinuria and is often associated with mental retardation,
although the complete syndrome is multifaceted and many individuals with this
disease are mentally normal. Some instances of genetic homocystinuria respond
favorably to pyridoxine therapy, suggesting that in these cases the defect in cystathionine
synthase is a decreased affinity for the cofactor. Missing or impaired cystathionase
leads to excretion of cystathionine in the urine but does not have any other
untoward effects. Rare cases are known in which cystathionase is
defective and operates at a low level. This genetic disease leads to
methioninuria with no other consequences.
Tyrosine Biosynthesis
Tyrosine is
produced in cells by hydroxylating the essential amino acid phenylalanine. This
relationship is much like that between cysteine and methionine. Half of the
phenylalanine required goes into the production of tyrosine; if the diet is
rich in tyrosine itself, the requirements for phenylalanine are reduced by
about 50%. Phenylalanine hydroxylase is a mixed-function
oxygenase: one atom of oxygen is incorporated into water and the other into the
hydroxyl of tyrosine. The reductant is the tetrahydrofolate-related cofactor tetrahydrobiopterin,
which is maintained in the reduced state by the NADH-dependent enzyme dihydropteridine
reductase.
Biosynthesis of tyrosine from phenylalanine
Missing or deficient
phenylalanine hydroxylase leads to the genetic disease known as phenlyketonuria
(PKU), which if untreated
leads to severe mental retardation. The mental retardation is caused by the
accumulation of phenylalanine, which becomes a major donor of amino groups in
aminotransferase activity and depletes neural tissue of -ketoglutarate. This absence of -ketoglutarate in the brain shuts down the TCA cycle and the associated production of aerobic energy,
which is essential to normal brain development.
The product
of phenylalanine transamination, phenylpyruvic acid, is reduced to
phenylacetate and phenyllactate, and all 3 compounds appear in the urine. The
presence of phenylacetate in the urine imparts a "mousy" odor. If the
problem is diagnosed early, the addition of tyrosine and restriction of
phenylalanine from the diet can minimize the extent of mental retardation.
In other
pathways, tetrahydrobiopterin is a cofactor. The effects of missing or
defective dihydropteridine reductase cause even more severe
neurological difficulties than those usually associated with PKU caused by
deficient hydroxylase activity.
Ornithine and Proline Biosynthesis
Glutamate is
the precursor of both proline and ornithine, with glutamate semialdehyde being
a branch point intermediate leading to one or the other of these 2 products.
While ornithine is not one of the 20 amino acids used in protein synthesis, it
plays a significant role as the acceptor of carbamoyl phosphate in the urea cycle. Ornithine serves an additional important role as the
precursor for the synthesis of the polyamines. The production of ornithine from glutamate is
important when dietary arginine, the other principal source of ornithine, is limited.
The fate of glutamate semialdehyde depends on prevailing cellular conditions.
Ornithine production occurs from the semialdehyde via a simple
glutamate-dependent transamination, producing ornithine.
Ornithine synthesis from glutamate
When arginine
concentrations become elevated, the ornithine contributed from the urea cycle plus that from glutamate semialdehyde inhibit the
aminotransferase reaction, with accumulation of the semialdehyde as a result.
The semialdehyde cyclizes spontaneously to 1pyrroline-5-carboxylate which
is then reduced to proline by an NADPH-dependent reductase.
The main
pathway to serine starts with the glycolytic intermediate 3-phosphoglycerate.
An
NADH-linked dehydrogenase converts 3-phosphoglycerate into a keto acid,
3-phosphopyruvate, suitable for subsequent transamination. Aminotransferase activity
with glutamate as a donor produces 3-phosphoserine, which is converted to
serine by phosphoserine phosphatase.
The main
pathway to glycine is a 1-step reaction catalyzed by serine
hydroxymethyltransferase.
This reaction
involves the transfer of the hydroxymethyl group from serine to the cofactor
tetrahydrofolate (THF), producing glycine and N5,N10-methylene-THF.
Glycine produced from serine or from the diet can also be oxidized by glycine
cleavage complex, GCC, to yield a second equivalent of N5,N10-methylene-tetrahydrofolate
as well as ammonia and CO2.
Glycine is
involved in many anabolic reactions other than protein synthesis including the
synthesis of purine nucleotides, heme, glutathione, creatine and serine.
Aspartate/Asparagine and
Glutamate/Glutamine Biosynthesis
Glutamate is
synthesized by the reductive amination of -ketoglutarate
catalyzed by glutamate dehydrogenase; it is thus a
nitrogen-fixing reaction. In addition, glutamate arises by aminotransferase
reactions, with the amino nitrogen being donated by a number of different amino
acids. Thus, glutamate is a general collector of amino nitrogen. Aspartate is
formed in a transamintion reaction catalyzed by aspartate transaminase,
AST. This reaction uses the aspartate -keto
acid analog, oxaloacetate, and glutamate as the amino donor. Aspartate can also
be formed by deamination of asparagine catalyzed by asparaginase.
Asparagine synthetase and glutamine synthetase,
catalyze the production of asparagine and glutamine from their respective amino acids. Glutamine is produced from glutamate by
the direct incorporation of ammonia; and this can be considered another
nitrogen fixing reaction. Asparagine, however, is formed by an amidotransferase
reaction. Aminotransferase reactions are readily reversible. The direction of
any individual transamination depends principally on the concentration ratio of
reactants and products. By contrast, transamidation reactions, which are
dependent on ATP, are considered irreversible. As a consequence, the
degradation of asparagine and glutamine take place by a hydrolytic pathway
rather than by a reversal of the pathway by which they were formed. As
indicated above, asparagine can be degraded to aspartate.
Amino Acid Catabolism
Glutamine/Glutamate and Asparagine/Aspartate
Catabolism
Glutaminase is an important kidney
tubule enzyme involved in converting glutamine (from liver and from other
tissue) to glutamate and NH3+, with the NH3+
being excreted in the urine. Glutaminase activity is present in
many other tissues as well, although its activity is not nearly as prominent as
in the kidney. The glutamate produced from glutamine is converted to -ketoglutarate, making glutamine a glucogenic amino
acid. Asparaginase is also widely distributed within the body,
where it converts asparagine into ammonia and aspartate. Aspartate
transaminates to oxaloacetate, which follows the gluconeogenic pathway to
glucose. Glutamate and aspartate are important in collecting and eliminating
amino nitrogen via glutamine synthetase and the urea cycle, respectively. The catabolic path of the carbon
skeletons involves simple 1-step aminotransferase reactions that directly
produce net quantities of a TCA cycle intermediate. The glutamate dehydrogenase
reaction operating in the direction of -ketoglutarate
production provides a second avenue leading from glutamate to gluconeogenesis.
Alanine is also important in intertissue nitrogen transport as part of the glucose-alanine cycle. Alanine's catabolic pathway involves a simple aminotransferase
reaction that directly produces pyruvate. Generally pyruvate produced by this
pathway will result in the formation of oxaloacetate, although when the energy
charge of a cell is low the pyruvate will be oxidized to CO2 and H2O
via the PDH complex and the TCA cycle. This makes alanine a glucogenic amino acid.
Arginine, Ornithine and
Proline Catabolism
The catabolism of arginine begins within the context of the urea cycle. It is
hydrolyzed to urea and ornithine by arginase. Ornithine, in
excess of urea cycle needs, is transaminated to form glutamate semialdehyde.
Glutamate semialdehyde can serve as the precursor for proline biosynthesis as
described above or it can be converted to glutamate. Proline catabolism is a
reversal of its synthesis process. The glutamate semialdehyde generated from
ornithine and proline catabolism is oxidized to glutamate by an ATP-independent
glutamate semialdehyde dehydrogenase. The glutamate can then be
converted to ketoglutarate in a transamination reaction. Thus
arginine, ornithine and proline, are glucogenic.
PAPS is used for the transfer of sulfate to biological molecules such as
the sugars of the glycosphingolipids.Other than protein, the most important product of
cysteine metabolism is the bile salt precursor taurine, which is used to
form the bile acid conjugates taurocholate and taurochenodeoxycholate.The
enzyme cystathionase can also transfer the sulfur from one
cysteine to another generating thiocysteine and pyruvate. Transamination of
cysteine yields -mercaptopyruvate which then reacts with sulfite, (SO32-),
to produce thiosulfate, (S2O32-) and pyruvate.
Both thiocysteine and thiosulfate can be used by the enzyme rhodanese
to incorporate sulfur into cyanide, (CN-), thereby detoxifying the cyanide
to thiocyanate.
The principal fates of the essential amino acid methionine are
incorporation into polypeptide chains, and use in the production of -ketobutyrate and cysteine via SAM as described above.
The transulfuration reactions that produce cysteine from homocysteine and
serine also produce -ketobutyrate, the latter being converted to
succinyl-CoA. Regulation of the methionine metabolic pathway is based on the
availability of methionine and cysteine. If both amino acids are present in
adequate quantities, SAM accumulates and is a positive effector on cystathionine
synthase, encouraging the production of cysteine and ketobutyrate (both of which are glucogenic). However,
if methionine is scarce, SAM will form only in small quantities, thus limiting cystathionine
synthase activity. Under these conditions accumulated homocysteine is
remethylated to methionine, using N5-methylTHF and other
compounds as methyl donors.
Valine, Leucine and Isoleucine
Catabolism
This group of essential amino acids are identified as the branched-chain
amino acids, BCAAs. Because this arrangement of carbon atoms cannot be made
by humans, these amino acids are an essential element in the diet. The
catabolism of all three compounds initiates in muscle and yields NADH and FADH2
which can be utilized for ATP generation. The catabolism of all three of these
amino acids uses the same enzymes in the first two steps. The first step in
each case is a transamination using a single BCAA aminotransferase,
with -ketoglutarate as amine acceptor. As a result, three
different -keto acids are produced and are oxidized using a
common branched-chain -keto acid dehydrogenase,
yielding the three different CoA derivatives. Subsequently the metabolic
pathways diverge, producing many intermediates. The principal product from
valine is propionylCoA, the glucogenic precursor of succinyl-CoA. Isoleucine
catabolism terminates with production of acetylCoA and propionylCoA; thus
isoleucine is both glucogenic and ketogenic. Leucine gives rise to acetylCoA
and acetoacetylCoA, and is thus classified as strictly ketogenic. There are a
number of genetic diseases associated with faulty catabolism of the BCAAs. The
most common defect is in the branched-chain -keto acid dehydrogenase. Since there is only one dehydrogenase enzyme for all
three amino acids, all three keto acids accumulate and are excreted in the urine.
The disease is known as Maple syrup urine
disease because of the
characteristic odor of the urine in afflicted individuals. Mental retardation
in these cases is extensive. Unfortunately, since these are essential amino
acids, they cannot be heavily restricted in the diet; ultimately, the life of
afflicted individuals is short and development is abnormal The main
neurological problems are due to poor formation of myelin in the CNS.
Phenylalanine and
Tyrosine Catabolism
Phenylalanine normally has only two fates: incorporation into polypeptide
chains, and production of tyrosine via the tetrahydrobiopterin-requiring phenylalanine
hydroxylase. Thus, phenylalanine catabolism always follows the pathway
of tyrosine catabolism. The main pathway for tyrosine degradation involves
conversion to fumarate and acetoacetate, allowing phenylalanine and tyrosine to
be classified as both glucogenic and ketogenic. Tyrosine is equally important
for protein biosynthesis as well as an intermediate in the biosynthesis of
several physiologically important metabolites e.g. dopamine, norepinephrine and
epinephrine (see Specialized
Products of Amino Acids). As
in phenylketonuria (deficiency of phenylalanine hydroxylase),
deficiency of tyrosine transaminase leads to urinary excretion of
tyrosine and the intermediates between phenylalanine and tyrosine. The adverse
neurological symptoms are the same for the two diseases. Genetic diseases (such
as various tyrosinemias and alkaptonuria) are also associated with other
defective enzymes of the tyrosine catabolic pathway. The first genetic disease
ever recognized, alcaptonuria, is caused by defective homogentisic acid
oxidase. Homogentisic acid accumulation is relatively innocuous,
causing urine to darken on exposure to air, but no life-threatening effects
accompany the disease. The other genetic deficiencies lead to more severe
symptoms, most of which are associated with abnormal neural development, mental
retardation, and shortened life span.
Lysine catabolism is unusual in the way that the -amino group is transferred to -ketoglutarate and into the general nitrogen pool. The
reaction is a transamination in which the -amino
group is transferred to the -keto carbon of -ketoglutarate
forming the metabolite, saccharopine. Unlike the majority of
transamination reactions, this one does not employ pyridoxal phosphate as a
cofactor. Saccharopine is immediately hydrolyzed by the enzyme -aminoadipic semialdehyde synthase in such a way that the amino nitrogen remains with
the -carbon of -ketoglutarate,
producing glutamate and -aminoadipic semialdehyde. Because this transamination
reaction is not reversible, lysine is an essential amino acid. The ultimate
end-product of lysine catabolism is acetoacetyl-CoA Genetic deficiencies in the
enzyme -aminoadipic semialdehyde synthase have been observed in individuals who excrete large
quantities of urinary lysine and some saccharopine. The lysinemia and
associated lysinuria are benign. Other serious disorders associated with lysine
metabolism are due to failure of the transport system for lysine and the other
dibasic amino acids across the intestinal wall. Lysine is essential for protein
synthesis; a deficiencies of its transport into the body can cause seriously
diminished levels of protein synthesis. Probably more significant however, is
the fact that arginine is transported on the same dibasic amino acid carrier,
and resulting arginine deficiencies limit the quantity of ornithine available
for the urea cycle. The result is severe hyperammonemia after a meal
rich in protein. The addition of citrulline to the diet prevents the
hyperammonemia. Lysine is also important as a precursor for the synthesis of carnitine,
required for the transport of fatty acids into the mitochondria for oxidation.
Free lysine does not serve as the precursor for this reaction, rather the
modified lysine found in certain proteins. Some proteins modify lysine to trimethyllysine
using SAM as the methyl donor to transfer methyl groups to the -amino of the lysine side chain. Hydrolysis of
proteins containing trimethyllysine provide the substrate for the subsequent
conversion to carnitine.
Histidine catabolism begins with release of the amino group catalyzed by histidase,
introducing a double bond into the molecule. As a result, the deaminated
product, urocanate, is not the usual -keto
acid associated with loss of -amino nitrogens. The end product of histidine
catabolism is glutamate, making histidine one of the glucogenic amino acids.
Another key feature of histidine catabolism is that it serves as a source of
ring nitrogen to combine with tetrahydrofolate (THF), producing the 1-carbon
THF intermediate known as N5-formiminoTHF. The latter
reaction is one of two routes to N5-formiminoTHF. The principal
genetic deficiency associated with histidine metabolism is absence or
deficiency of the first enzyme of the pathway, histidase. The
resultant histidinemia is relatively benign. The disease, which is of
relatively high incidence (
Tryptophan Catabolism
A number of important side reactions occur during the catabolism of
tryptophan on the pathway to acetoacetate. The first enzyme of the catabolic
pathway is an iron porphyrin oxygenase that opens the indole ring. The latter
enzyme is highly inducible, its concentration rising almost 10-fold on a diet
high in tryptophan. Kynurenine is the first key branch point
intermediate in the pathway. Kynurenine undergoes deamniation in a standard
transamination reaction yielding kynurenic acid. Kynurenic acid and
metabolites have been shown to act as antiexcitotoxics and anticonvulsives. A
second side branch reaction produces anthranilic acid plus alanine. Another
equivalent of alanine is produced further along the main catabolic pathway, and
it is the production of these alanine residues that allows tryptophan to be
classified among the glucogenic and ketogenic amino acids. The second important
branch point converts kynurenine into 2-amino-3-carboxymuconic semialdehyde,
which has two fates. The main flow of carbon elements from this intermediate is
to glutarate. An important side reaction in liver is a transamination and
several rearrangements to produce limited amounts of nicotinic acid,
which leads to production of a small amount of NAD+ and NADP+
Aside form its role as an amino acid in protein biosynthesis, tryptophan also
serves as a precursor for the synthesis of serotonin and melatonin.
These products are discussed in Specialized
Products of Amino Acids