BIOLOGICAL OXIDATION. ENERGY METABOLISM.
SUBSTRATE AND OXIDATIVE PHOSPHORYLATION
Bioenergetic
Bioenergetics is the part of biochemistry
concerned with the energy involved in making and breaking of chemical bonds in
the molecules
found in biological organisms.
Living organisms produce ATP from energy sources via oxidative phosphorylation. The terminal
phosphate bonds of ATP are relatively weak compared with the stronger bonds
formed when ATP is broken down to adenosine monophosphate and phosphate,
dissolved in water. Here it is the energy of hydration that results in energy
release. This hydrolysis of ATP is used as a battery to store energy in cells,
for intermediate metabolism. Utilization of chemical energy from such molecular
bond rearrangement powers biological processes in every biological organism.
Exergonic
and endergonic processes. Mechanism of energy releasing and storage in the organism.
Exergonic refers to chemical reactions that proceed spontaneously
from reactants to products with the release of energy. Endergonic reactions
require energy input to proceed. Although the terms are often used rather
loosely, they are precisely defined thermodynamic concepts based on changes in
an entity called Gibbs free energy (G) accompanying reactions. Reactions in
which -G decreases are exergonic, and those in which -G increases are
endergonic. Exergonic reactions often involve the breakdown of organic compounds
found in food, whereas endergonic reactions frequently entail synthesis of
complicated molecules.
Biological metabolism contains many
examples of both types, and living organisms have developed elaborate
techniques for coupling the two.
By
coupling exergonic and endergonic reactions, organisms are able to use the
available energy in food they consume to construct complex proteins, lipids,
nucleic acids and carbohydrates needed for their growth and development. A
well-known example involves coupling the formation of energy-rich adenosine
triphosphate (ATP) from adenosine diphosphate (ADP) and phosphate (an
endergonic reaction), with the transfer of hydrogen, removed from organic food
materials, to oxygen (an exergonic reaction). The process is called oxidative
phosphorylation. Energy stored in ATP may be used subsequently when the
exergonic conversion of ATP back to ADP and phosphate is coupled with the
endergonic synthesis of a needed cellular component.
What is macroergic bond? Examples of high
energy compounds.
A bond in chemical compounds, which acts as an energy accumulator. Macroergic bond
is present in some phosphorus-containing
compounds in living organisms, e. g.* adenosinetriphosphate.
Macroergic bonds
are formed as a
result of complex biochemical processes and break
up when energy is released. The processes are reversible and can be repeated.
High-energy
phosphate can mean one of two things:
·
The
phosphate-phosphate bonds formed when compounds such as adenosine diphosphate
and adenosine triphosphate are created.
·
The compounds
that contain these bonds, which include the nucleoside
diphosphates and nucleoside triphosphates, and the high-energy storage
compounds of the muscle, the phosphagens. When people speak of a high-energy phosphate
pool, they speak of the total concentration of these compounds with these
high-energy bonds.
ATP is often called a high energy compound and its
phosphoanhydride bonds are referred to as high-energy bonds. There is nothing
special about the bonds themselves. They are high-energy bonds in the sense
that free energy is released when they are hydrolyzed, for the reasons
given above.
The term 'high energy' with respect to these bonds can be
misleading because the negative free energy change is not due directly to the
breaking of the bonds themselves. The breaking of these bonds, as with the
breaking of most bonds, is an endergonic step (i.e., it absorbs energy, not
releases it). The negative free energy change comes instead from the fact that
the bonds formed after hydrolysis-or the phosphorylation of a residue by
ATP-are lower in energy than the bonds present before hydrolysis (this includes
all of the bonds involved in the reaction, not just the phosphate bonds
themselves). This effect is due to a number of factors including increased resonance stabilization and solvation
of the products relative to the reactants.
ATP
formation
The ATP is used for many cell functions including transport
work moving substances across cell membranes. It is also used for mechanical
work, supplying the energy needed for muscle contraction. It supplies
energy not only to heart muscle (for blood circulation) and skeletal muscle
(such as for gross body movement), but also to the chromosomes and flagella to
enable them to carry out their many functions. A major role of ATP is in chemical
work, supplying the needed energy to synthesize the multi-thousands of
types of macromolecules that the cell needs to exist.
Adenosine
triphosphate (ATP) is an organic molecule which stores
energy used to carry out life processes. ATP is made of
an adenine nucleoside, ribose sugar, and three phosphate groups. The high
energy bonds between phosphate groups are broken when hydrolyzed, thus
releasing energy in the system. Either one or two phosphate groups can break
off, releasing Gibb's free energy,
which can then be used to drive other reactions.
Substrate-level and
oxidative phosphorylation
Substrate-level phosphorylation
is a type of metabolic reaction that results in the formation of adenosine
triphosphate (ATP) or guanosine
triphosphate (GTP) by the direct transfer and
donation of a phosphoryl
(PO3) group to adenosine
diphosphate (ADP) or guanosine diphosphate
(GDP) from a phosphorylated reactive
intermediate. Note that the phosphate group does
not have to come directly from the substrate. By convention, the phosphoryl
group that is transferred is referred to as a phosphate group.
An alternative way to create ATP is through oxidative
phosphorylation, which takes place during the
process of cellular
respiration, in addition to the substrate-level
phosphorylation that occurs during glycolysis and the Krebs cycle. During oxidative
phosphorylation, NADH is oxidized to NAD+, yielding 2.5 ATPs, and
FADH2 yields 1.5 ATPs when it is oxidized. Oxidative phosphorylation
uses an electrochemical or chemiosmotic gradient of protons (H+)
across the inner mitochondrial membrane to generate ATP from ADP, which is a
key difference from substrate-level phosphorylation.
The main part of substrate-level phosphorylation
occurs in the cytoplasm of cells as part of glycolysis
and in mitochondria as part of the Krebs Cycle under both aerobic
and anaerobic
conditions. In the pay-off phase of
glycolysis, two ATP are produced by
substrate-level phosphorylation: two and only two 1,3-bisphosphoglycerate
are converted to 3-phosphoglycerate by transferring a
phosphate group to ADP by a kinase; two phosphoenolpyruvate are converted to pyruvate
by the transfer of their phosphate groups to ADP by another kinase. The first
reaction occurs after the generation of 1,3-bisphosphoglycerate
from 3-phosphoglyceraldehyde and an organic phosphate via a dehydrogenase.
ATP is generated in a following separate step (key difference from oxidative
phosphorylation) by transfer of the high-energy phosphate on 1,3-bisphosphoglycerate to ADP via the enzyme phosphoglycerate kinase,
generating 3-phosphoglycerate. As ATP is formed of a former inorganic phosphate
group, this step leads to the energy yield of glycolysis. The second
substrate-level phosphorylation occurs later by means of the reaction of
phosphenolpyruvate (PEP) to pyruvate via the pyruvate kinase.
This reaction regenerates the ATP that has been used in the preparatory phase
of glycolysis to activate glucose to glucose-6-phosphate and
fructose-6-phosphate to fructose-1,6-bisphosphate,
respectively.
ATP can be
generated by substrate-level phosphorylation in the mitochondrial matrix, a
pathway that
is independent from the protonmotive force, pmf. In the mitochondrial matrix
there are two reactions capable of substrate-level phosphorylation: the
mitochondrial phosphoenolpyruvate carboxykinase (PEPCK), and the succinate-CoA
ligase (SUCL or succinate thiokinase or succinyl-CoA synthetase).
Another
form of substrate-level phosphorylation is also seen in working skeletal
muscles and the brain. Phosphocreatine is stored as
a readily available high-energy phosphate supply, and the enzyme creatine
phosphokinase transfers a phosphate from
phosphocreatine to ADP to produce ATP. Then the ATP releases giving chemical
energy. Apart from this substrate-level phosphorylation can also be observed in
fermentation,
for example, heterolactic
fermentation, butyric acid fermentation, and
propanoic acid fermentation.
The modern views on the biological
oxidation
Biological oxidation is that
oxidation which occurs in biological systems to produce energy.
Oxidation can occur by:
1-Addition of oxygen (less
common)
2-Removal of hydrogen (common)
3-Removal of electrons (most
common)
Electrons are not stable in the free
state, so their removal form a substance
(oxidation) must be accompanied by their acceptance by another substance
(reduction) hence the reaction is called oxidation-reduction reaction or redox
reaction and the involved enzymes are called oxido-reductases
Composition of respiratory chain
NADH
dehydrogenase (EC 1.6.5.3) (also
referred to as "NADH:quinone reductase" or "Complex I") is
an enzyme located in
the inner mitochondrial
membrane that catalyzes the transfer of electrons from NADH to coenzyme Q (CoQ). It is
the "entry enzyme" of oxidative
phosphorylation in the mitochondria. [1]
NADH
Dehydrogenase is the first enzyme (Complex I) of the mitochondrial electron
transport chain. There are three energy-transducing
enzymes in the electron transport chain - NADH dehydrogenase (Complex I), Coenzyme Q –
cytochrome c reductase (Complex III), and cytochrome c
oxidase (Complex IV). [2] NADH
dehydrogenase is the largest and most complicated enzyme of the electron
transport chain.[3].
FADH
dehydrogenase
In
biochemistry, flavin
adenine dinucleotide (FAD) is a redox cofactor
involved in several important reactions in metabolism. FAD can
exist in two different redox states, which it converts between by accepting or
donating electrons. The molecule consists of a riboflavin moiety
(vitamin B2) bound to the phosphate group of an ADP
molecule. The flavin group is bound to ribitol, a sugar
alcohol, by a carbon-nitrogen bond, not a glycosidic bond. Thus,
riboflavin is not technically a nucleotide; the name flavin adenine
dinucleotide is a misnomer.[1]
FAD
can be reduced to FADH2, whereby it
accepts two hydrogen atoms (a net gain of two electrons):
Ubiquinones
These
molecules are also known as coenzyme Q or mitoquinones. They are involved in
electron transport in mitochondrial preparations playing an essential role in the
oxidation of succinate or NADH via the cytochrome system. They serves not only as a coenzyme but also, in their reduced
forms, as antioxidants. They are synthesized de novo in all animal tissues and
cannot thus be regarded as vitamins. Ubiquinones are present in all aerobic
organisms, plants, animals (the name ubiquinone was proposed with reference to
their ubiquitous occurrence) and bacteria, but are absent from Gram-positive
eubacteria and the archaebacteria. They were discovered by the Morton's group
in animal fat but their quinonoid structure was revealed by Crane two years
later in extracts from beef heart mitochondria. The compound had a 2,3-dimethoxy-5-methylbenzoquinone nucleus and a side chain
of 10 isoprenoid units and
was referred to as coenzyme Q 10 .
Cytochromes
are, in general, membrane-bound (i.e. inner mitochondrial membrane) hemeproteins
containing heme
groups and are primarily responsible for the generation of ATP
via electron transport.
They are
found either as monomeric proteins (e.g., cytochrome c)
or as subunits of bigger enzymatic complexes that
catalyze redox
reactions.
In the
process of oxidative phosphorylation, which
is the principal energy-generating process undertaken by organisms, other
membrane-bound and -soluble complexes and cofactors are involved
in the chain of redox reactions, with the additional net effect that protons (H+)
are transported across the mitochondrial inner membrane. The resulting transmembrane proton gradient
([protonmotive force]) is used to generate ATP, which is
the universal chemical energy currency of life. ATP is consumed to drive cellular
processes that require energy (such as synthesis of macromolecules, active
transport of molecules across the membrane, and assembly of flagella).
Respiratory chain
The
system of mitochondrial enzymes and redox carrier molecules which ferry
reducing equivalents from substrates to oxygen are collectively known as the electron
transport system, or the respiratory chain. This system captures the free energy available from
substrate oxidation so that it may later be applied to the synthesis of ATP.
Complex
I and Complex II direct electrons to coenzyme Q. Complex I, also called
NADH-coenzyme Q reductase, accepts electrons from NADH. The NADH releases a
proton and two electrons. The electrons flow through a flavoprotein containing
FMN and an iron-sulfur protein. First, the flavin coenzyme (flavin
mononucleotide) and then the iron-sulfur center undergo cycles of reduction and
then oxidation, transferring their electrons to a quinone molecule, coenzyme
Q .
Complex I is capable of transferring protons from the
matrix to the intermembrane space while undergoing these redox cycles. One
possible source of the protons is the release of a proton from NADH as it is
oxidized to NAD, although this is not the only explanation. Apparently,
conformational changes in the proteins of Complex I also are
involved in the mechanism of proton translocation during electron transport.
Complex II,
also known as succinate-coenzyme Q reductase, accepts electrons from succinate
formed during the TCA cycle. Electrons flow from succinate to FAD (the
flavin-adenine dinucleotide) coenzyme, through an iron-sulfur protein and a
cytochrome b550 protein (the number refers to the wavelength where
the protein absorbs), and to coenzyme Q. No protons are translocated by Complex
II. Because translocated protons are the source of the energy for ATP
synthesis, this means that the oxidation of a molecule of FADH2
inherently leads to less ATP synthesized than does the oxidation of a molecule
of NADH. This experimental observation also fits with the difference in the
standard reduction potentials of the two molecules. The reduction potential of
FAD is -0.22 V, as opposed to -0.32 V for NAD.
Coenzyme Q is
capable of accepting either one or two electrons to form
either a semiquinone or hydroquinone form. Coenzyme Q is not
bound to a protein; instead it is a mobile electron carrier and can float
within the inner membrane, where it can transfer electrons from Complex I and
Complex II to Complex III.
Complex III
is also known as coenzyme Q-cytochrome c reductase. It accepts
electrons from reduced coenzyme Q, moves them within the complex through two
cytochromes b, an iron-sulfur protein, and cytochrome c1. Electron
flow through Complex II transfers proton(s) through the membrane into the
intermembrane space. Again, this supplies energy for ATP synthesis. Complex III
transfers its electrons to the heme group of a small, mobile electron transport
protein, cytochrome c.
Cytochrome c
transfers its electrons to the final electron transport component, Complex
IV, or cytochrome oxidase. Cytochrome oxidase
transfers electrons through a copper-containing protein, cytochrome a, and
cytochrome a3, and finally to molecular oxygen. The
overall pathway for electron transport is therefore:
The
number n is a fudge factor to account for the fact that the exact
stoichiometry of proton transfer isn't really known. The important point is
that more proton transfer occurs from NADH oxidation than from FADH2
oxidation.
A theory postulated by the biochemist Peter Mitchell in 1961
to describe ATP synthesis by way of a proton electrochemical coupling is called
chemiosmotic hypothesis.
In the 1960s,
ATP
was known to be the energy currency of life, but the mechanism by which ATP was
created in the mitochondria was assumed
to be by substrate-level
phosphorylation. Mitchell's chemiosmotic hypothesis
was the basis for understanding the actual process of oxidative
phosphorylation. At the time, the biochemical
mechanism of ATP synthesis by oxidative phosphorylation was unknown.
Mitchell
realised that the movement of ions across an electrochemical
membrane potential could provide the energy needed to
produce ATP. His hypothesis was derived from information that was well known in
the 1960s. He knew that living cells had a membrane potential;
interior negative to the environment. The movement of charged ions across a
membrane is thus affected by the electrical forces (the attraction of positive
to negative charges). Their movement is also affected by thermodynamic
forces, the tendency of substances to diffuse from regions
of higher concentration. He went on to show that ATP synthesis was coupled to
this electrochemical
gradient.
Because the structures seen in EM,
the subunit composition, and the sequences of the subunits appeared to be so
similar, it had been assumed that the mechanisms, and hence the
stoichiometries, would be the same. In this context, the evidence suggesting
that the stoichiometry of H+/ATP (n above) varied depending on
system was surprising. Values based on measure ATP/2e- ratios, and H+/2e-
ratios had suggested that n was 3 for mitochondria, and 4 for chloroplasts, but
these values were based on the assumption of integer stoichiometries. Although
all the F1F0-type ATP-synthases likely had a common
origin, both the assumption that the stoichiometries are the same, and that n
is integer, are called into question by emerging structural data (see below).
The ATP synthase operates through a mechanism in which the
three active sites undergo a change in binding affinity for the reactants of
the ATP-ase reaction, ATP, ADP and phosphate, as originally predicted by Paul Boyer. The change in affinity
accompanies a change in the position of the g-subunit relative to the a, b-ring,
which involves a rotation of the one relative to the other. In the direction of
ATP synthesis, the rotation is driven by a flux of H+ down the
proton gradient, through a coupling between the g-subunit, and the c-subunit of FO. This
rotation has now been demonstrated experimentally.
Respiratory control
The dependence of oxidative
phosphorylation on ADP reveals an important general feature of this process: Respiration
is tightly coupled to the synthesis of ATP. Not only is ATP synthesis
absolutely dependent on continued electron flow from substrates to oxygen, but
electron flow in normal mitochondria occurs only when ATP is being synthesized
as well. This regulatory phenomenon, called respiratory control, makes
biological sense, because it ensures that substrates will not be oxidized
wastefully. Instead, their utilization is controlled by the physiological need
for ATP.
In most aerobic cells the level of
ATP exceeds that of ADP by 4- to 10-fold. Respiration depends on ADP as
a substrate for phosphorylation. When ATP is consumed at high rates,
accumulation of ADP stimulates respiration, with concomitant activation of ATP
resynthesis. Conversely, in a relaxed and well-nourished cell, ATP accumulates
at the expense of ADP, and the depletion of ADP limits the rate of both
electron transport and its own phosphorylation to ATP. Thus, the energy-generating
capacity of the cell is closely attuned to its energy demands.
Inhibitors of tissue respiration
Chemiosmosis can be disrupted by a variety of
chemicals. In oxidative phosphorylation, some of these inhibitors are quite
infamous:
The electron transport chain
was determined by studying the effects of particular inhibitors.
Rotenone is a common
insecticide that strongly inhibits the electron transport of complex I.
Rotenone
is a natural product obtained from the roots of several species of plants.
Tribes in cert
ain parts of the world beat the
roots of trees along riverbanks to release rotenone into the water which
paralyzes fish and makes them easy prey.
Amytal
is a barbiturate that inhibits the electron transport of complex I. Demerol is
painkiller that also inhibits complex
Antibiotic. Induces apoptosis, which is not prevented by the presence of Bcl-2.
Inhibits mitochondrial electron transport specifically
between cytochromes b and c1.
All
three of these complex I inhibitors block the oxidation of the Fe-S clusters of
complex I.
2-Thenoyltrifluoroacetone
and carboxin specifically block electron transport in Complex II
Antimycin
A is an antibiotic that inhibits electron transfer in complex III by blocking
the transfer of electrons between Cyt bH and coenzyme
Q bound at the QN site. Antibiotic. Induces
apoptosis, which is not prevented by the presence of Bcl-2. Inhibits mitochondrial electron transport specifically between
cytochromes b and c1.
Cyanide,
azide and carbon monoxide all inhibit electron transport in Complex IV. The all
inhibit
electron transfer by
binding tightly with the iron coordinated in Cyt a
The coupling between electron transport and oxidative phosphorylation
depends on the impermeability of the inner mitochondrial membrane to
H+translocation. The only way for protons to go from the intermembrane space to
the matrix is through ATP synthase. Uncouplers uncouple electron transport from
oxidative phosphorylation. They collapse the chemiosmotic gradient by
dissipating protons across the inner mitochondrial membrane. All of the
uncouplers shown to the left, collapse the pH gradient by binding a proton on
the acidic side of the membrane, diffusing through the inner mitochondrial
membrane and releasing the proton on the membranes alkaline side.
Uncouplers
of oxidative phosphorylation stimulate the rate of electron flow but not
ATP synthesis.
(a)At
relatively low levels of an uncoupling agent, P/O ratios drop somewhat, but the
cell can compensate for this by increasing the rate of electron flow; ATP
levels can be kept relatively normal. At high levels of uncoupler, P/O ratios
approach zero and the cell cannot maintain ATP levels.
(b)
As amounts of an uncoupler increase, the P/O ratio decreases and the body
struggles to make sufficient ATP by oxidizing more fuel. The heat produced by
this increased rate of oxidation raises the body temperature. The P/O ratio is
affected as noted in (a).
(c)
Increased activity of the respiratory chain in the presence of an uncoupler
requires the degradation of additional energy stores (glycogen and fat). By
oxidizing more fuel in an attempt to produce the same amount of ATP, the
organism loses weight. If the P/O ratio nears zero, the lack of ATP will be
lethal
2,4-Dinitrophenol, dicumarol and carbonyl
cyanide-p-trifluorocarbonyl-cyanide methoxyphenyl hydrazone (FCCP) all have hydrophobic
character making them soluble in the bilipid membrane. All of these decouplers
also have dissociable protons allowing them to carry protons from the
intermembrane space to the matrix which collapses the pH gradient. The
potential energy of the proton gradient is lost as heat DNP is a
chemical uncoupler of electron
transport and oxidative
phosphorylation.
DNP
permeabilizes the inner mitochondrial membrane to protons, destroying the
proton gradient and, in doing so, uncouples the electron transport system from
the oxidative phosphorylation. In this situation, electrons continue to pass
through the electron transport system and reduce oxygen to water, but ATP
is not synthesized in the process. The compound, trifluorocarbonylcyanide
phenylhydrazone (FCCP),
is also an uncoupler.
The link between electron transport and ATP synthesis is below. (a) In
the presence of excess phosphate and substrate and intact mitochondria, oxygen
is consumed only when ADP is added. When all of the added ADP has been
converted into ATP, electron transport stops and oxygen consumption ceases. (b)
The addition of 2,4-dintrophenol uncouples electron
transfer from ATP synthesis.
An uncoupling protein
(also called thermogenin) is produced in brown adipose tissue of newborn
mammals and hibernating mammals.
Valinomycin combines
with K ions to form a complex that passes through the inner
Valinomycin
is a potent antibiotic which acts as a potassium (K+) ionophore. Induces K+ conductivity in cell membranes. Also active in vitro against Mycobacterium Tuberculosis, and as an
apoptosis inducer.
Oligomycin
is a natural antibiotic isolated from Streptomyces diastatochromogenes which
inhibits mitochondrial H+-ATP synthase. It is primarily found to act
as an inhibitor of mitochondrial respiration and swelling. This
antibiotic is widely used as an inhibitor of oxidative phosphorylation.1-2
Oligomycin inhibits the H+- ATP-synthase by binding to the
Oligomycin sensitivity-conferring protein (OSCP) at the F(o)
subunits 6 and 9 which are found in the stalk of the F1F0-ATPase
complex. This binding blocks the proton conductance and inhibits the synthesis
of mitochondrial ATP. Because of its activity, it can also be used to reduce
the number of parameters (such as ER Ca2+ release,
exocytotoxicity and apopotosis) which are affected by mitochondrial depolarization.
Cytochrome P450
The active
site of cytochrome P450 contains a heme iron center. The iron
is tethered to the P450 protein via a thiolate ligand derived from a cysteine residue. This cysteine and several
flanking residues are highly conserved in known CYPs and have the formal PROSITE signature consensus pattern [FW] -
[SGNH] - x - [GD] - {F} - [RKHPT] - {P} - C - [LIVMFAP] - [GAD].[7] Because of the vast variety of
reactions catalyzed by CYPs, the activities and properties of the many CYPs
differ in many aspects. In general, the P450 catalytic cycle proceeds as
follows:
1.
The substrate binds to the active
site of the enzyme, in close proximity to the heme group, on the side opposite
to the peptide chain. The bound substrate induces a change in the conformation
of the active site, often displacing a water molecule from the distal axial
coordination position of the heme iron, and sometimes changing the state of the
heme iron from low-spin to high-spin.[9] This gives rise to a change in
the spectral properties of the enzyme, with an increase in absorbance at
390 nm and a decrease at 420 nm. This can be measured by difference
spectrometry and is referred to as the "type I" difference
spectrum. Some substrates cause an opposite change in spectral properties, a
"reverse type I" spectrum, by processes that are as yet unclear.
Inhibitors and certain substrates that bind directly to the heme iron give rise
to the type II difference spectrum, with a maximum at 430 nm and a
minimum at 390 nm (see inset graph in figure). If no reducing equivalents
are available, this complex may remain stable, allowing the degree of binding
to be determined from absorbance measurements in vitro/ The change in the electronic state of the
active site favors the transfer of an electron from NAD(P)H
via cytochrome
P450 reductase or another associated reductase.
This takes place by way of the electron transfer chain, as described above,
reducing the ferric heme iron to the ferrous state.
2.
Molecular oxygen binds covalently to
the distal axial coordination position of the heme iron. The cysteine ligand is
a better electron donor than histidine, which is normally found in heme-containing
proteins. As a consequence, the oxygen is activated to a greater extent than in
other heme proteins. However, this sometimes allows the iron-oxygen bond to
dissociate, causing the so-called "uncoupling reaction", which
releases a reactive superoxide radical and interrupts the catalytic cycle.
3. A second electron is transferred via the electron-transport system, from either cytochrome
Free Radicals: Atoms contain a nucleus, and electrons move around the nucleus, usually
in pairs. A free radical is any atom or molecule that contains one or more
unpaired electrons. The unpaired electrons alter the chemical reactivity
of an atom or molecule, usually making it more reactive than the corresponding
non-radical. However, the actual chemical reactivity of radicals varies
enormously.
Free radicals and diseases: Free
radicals are capable of damage biomolecules, provoke immune response, activate
oncogens, cause atherogenesis and enhance ageing process.
Free radicals with pollutants: Highly reactive
molecules called free radicals can cause tissue damage by reacting with
polyunsaturated fatty acids in cellular membranes, nucleotides in DNA, and
critical sulfhydryl bonds in proteins. Free radicals can originate endogenously
from normal metabolic reactions or exogenously as components of tobacco smoke
and air pollutants and indirectly through the metabolism of certain solvents,
drugs, and pesticides as well as through exposure to radiation. There is some
evidence that free radical damage contributes to the etiology of many chronic
health problems such as emphysema, cardiovascular and inflammatory diseases,
cataracts, and cancer. Defenses against free radical damage include tocopherol
(vitamin E), ascorbic acid (vitamin C), beta-carotene, glutathione, uric acid,
bilirubin, and several metalloenzymes including glutathione peroxidase
(selenium), catalase (iron), and superoxide dismutase (copper, zinc, manganese)
and proteins such as ceruloplasmin (copper).