BIOCHEMISTRY
OF MUSCLES, MUSCLE CONTRACTION. BIOCHEMISTRY OF CONNECTIVE TISSUE
Muscle
Muscle (from Latin musculus "little mouse" is contractile tissue of the body and is derived from the mesodermal layer of embryonic germ cells.
It is classified as:
skeletal, cardiac, or smooth muscle.
Function of muscle is to
produce force and cause motion,
either locomotion or movement within internal organs. Much of muscle contraction occurs without consciousthought
and is necessary for survival, like the contraction of the heart,
or peristalsis (which pushes food through the digestive system).
Voluntary muscle contraction is used to move the body, and can be finely
controlled, like movements of the eye, or gross movements like the quadriceps muscle of the thigh.
Muscular System
There are two broad types of
voluntary muscle fibers, slow twitch and fast twitch. Slow twitch fibers
contract for long periods of time but with little force while fast twitch
fibers contract quickly and powerfully but fatigue very rapidly.
The muscular system includes three
types of muscles. They are smooth, which are found on the walls of internal
organs, cardiac, which is found only in the heart, and skeletal muscles, which
help strenthen the body and connect to bones.
There are three types of muscle:
Skeletal muscle or "voluntary muscle" is anchored by tendons to bone and is used to affect skeletal movement such as locomotion and in maintaining posture. Though this postural control is generally
maintained as a subconscious reflex, the muscles responsible react to conscious
control like non-postural muscles. An average adult male is made up of 40-50%
of skeletal muscle and an average adult female is made up of 30-40%.
Skeletal muscle is a type of striated muscle,
which usually attaches to tendons. Skeletal muscles are used to create
movement, by applying force to bones and joints viacontraction. They generally
contract voluntarily (via somatic nerve stimulation), although they can
contract involuntarily through reflexes. The whole muscle is wrapped in a
special type of connective tissue, epimysium.
Structure and
functions of myofibril proteins
(myosine, actine,
actomyosine, troponine, tropomyosine).
Arrangement of
thin and thick filaments in a myofibril:
The thin and thick filaments are organized into neat bundles called sarcomeres.
Here is the image
of the thick and thin filaments together:
1. A sarcomere runs from Z-line to
Z-line.
2. Sarcomeres run along the longitudinal
axis of the muscle fiber.
Putting the
myofibrils back into the muscle fiber...
Mechanism of
muscle’s contraction and relaxation. Role of calcium and ATP.
Energetic
providing of muscle’s work.
· cellular respiration in the mitochondria of the fibers.
Creatine
phosphate + ADP ↔ creatine + ATP
However,
this source is limited and eventually the muscle must depend on cellular
respiration.
Properties
of White and Red Muscles
Peculiarities of metabolism in cardiac
muscle.
The
long plateau of the action potential in cardiac muscle serves two functions: It
provides a more prolonged contraction without resorting to tetanus, and it
provides a longer refractory period to prevent the heart from contracting
prematurely. This plateau is produced by a number of factors, the most
important of which is a decrease in potassium conductance with
hypopolarization, followed by a slowly developing increase that brings the
potassium conductance to a final value just slightly greater than resting
levels in Purkinje fibers and to resting levels in contractile cells in about
300 msec. A change in membrane conductance with changes in membrane potential
is called rectification by biophysicists. This change in potassium conductance
is called anomalous rectification.
Some signs and symptoms of kidney dysfunction
include:
Fatigue,
lack of concentration, poor appetite or trouble sleeping
Urine
that is foamy, bloody, or coffee-coloured
A
decrease in the amount of urine
Mid-back
pain (flank), below the ribs, near where the kidneys are located
What
does the test result mean?
prostate
disease, kidney stone, or other causes of urinary tract obstruction; or
Since
creatinine levels are in proportion to muscle mass, women tend to have lower
levels than men.
Diagnostic
significance of determination of creatin phosphokinase’s activity(CK)
Lowered
CK can be an indication of alcoholic liver disease and rheumatoid arthritis.
Connective tissue
Connective tissue (CT) is a kind
of biological tissue that supports, connects, or separates different types of
tissues and organs of the body. It is one of the four general classes of
biological tissues—the others of which are epithelial, muscular, and nervous
tissues.
All CT has three main
components: cells, fibers, and extracellular matrices, all immersed in the body
fluids.
Connective tissue can be
broadly subdivided into connective tissue proper, special connective tissue,
and series of other, less classifiable types of connective tissues. Connective
tissue proper consists of loose connective tissue and dense connective tissue
(which is further subdivided into dense regular and dense irregular connective
tissues.) Special connective tissue consists of reticular connective tissue,
adipose tissue, cartilage, bone, and blood. Other kinds of connective tissues
include fibrous, elastic, and lymphoid connective tissues.
Fibroblasts are the cells
responsible for the production of some CT.
Type-I collagen, is present
in many forms of connective tissue, and makes up about 25% of the total protein
content of the mammalian body.
BIOMEDICAL IMPORTANCE
Most mammalian cells are located in tissues where
they are surrounded by a complex extracellular matrix (ECM) often
referred to as “connective tissue.” The ECM contains three major classes
of biomolecules:
(1)the structural proteins, collagen,
elastin, and fibrillin;
(2) certain specialized proteins such as fibrillin,
fibronectin, and laminin; and
(3) proteoglycans, whose chemical natures
are described below.
The extracellular matrix
The ECM has been found to be involved in many normal
and pathologic processes—eg, it plays
important roles in development, in inflammatory states, and in the spread of
cancer cells. Involvement of certain components of the ECM has been documented
in both rheumatoid arthritis and osteoarthritis. Several diseases (eg,
osteogenesis imperfecta and a number of types of the Ehlers-Danlos syndrome)
are due to genetic disturbances of the synthesis of collagen. Specific
components of proteoglycans (the glycosaminoglycans; GAGs) are affected in the
group of genetic disorders known as the mucopolysaccharidoses.
Changes occur in the ECM during the aging
process. This chapter describes the basic biochemistry of the three major
classes of biomolecules found in the ECM and illustrates their biomedical
significance.
Major biochemical features of two specialized
forms of ECM—bone and cartilage—and of a number of diseases involving them are
also briefly considered.
Functions of connective tissue
- Storage of energy
- Protection of organs
- Provision of structural framework
for the body
- Connection of body tissues
- Connection of epithelial
tissues to muscle tissues
Characteristics
of connective tissue and fiber types
Cells are spread through an extracellular fluid.
Ground substance - A clear, colorless, and viscous
fluid containing glycosaminoglycans and proteoglycans to fix the bodywater and
the collagen fibers in the intercellular spaces. Ground substance slows the
spread of pathogens.
Fibers. Not all types of CT are fibrous. Examples include
adipose tissue and blood. Adipose tissue gives "mechanical
cushioning" to our body, among other functions. Although there is no dense
collagen network in adipose tissue, groups of adipose cells are kept together
by collagen fibers and collagen sheets in order to keep fat tissue under
compression in place (for example, the sole of the foot). The matrix of blood
is plasma.
Both the ground substance and proteins (fibers)
create the matrix for CT.
Types of fibers:Tissue → Purpose → Components → Location
Collagenous fibers → Alpha
polypeptide chains → tendon, ligament, skin, cornea, cartilage, bone,
blood vessels, gut, and intervertebral disc.
Elastic fibers → elastic
microfibril & elastin → extracellular
matrix
Reticular fibers → Type-III
collagen → liver, bone marrow,
lymphatic organs.
Structure and functions of collagen.
Collagen is a group of naturally occurring proteins
found in animals,
especially in the flesh and connective
tissues of vertebrates.
It is the main
component of connective tissue, and is the most abundant
protein in mammals, making up about 25% to 35% of the whole-body protein
content. Collagen, in the form of elongated fibrils, is
mostly found in fibrous tissues such as tendon, ligament
and skin, and is also abundant in cornea, cartilage, bone, blood vessels, the
gut, and intervertebral disc. The fibroblast
is the most common cell which creates collagen. In muscle tissue, it serves as
a major component of the endomysium.
Fig.Functions of collagen
Collagen constitutes
one to two percent of muscle tissue, and accounts for 6% of the weight of
strong, tendinous muscles. Gelatin, which is used in food and industry, is collagen that
has been irreversibly hydrolyzed. Collagen is composed of a triple helix, which
generally consists of two identical chains (α1) and an additional chain
that differs slightly in its chemical composition (α2). The amino acid
composition of collagen is atypical for proteins, particularly with respect to
its high hydroxyproline content. The most common motifs
in the amino acid sequence of collagen are glycine-proline-X
and glycine-X-hydroxyproline, where X is any amino acid other than glycine,
proline or hydroxyproline.
Figure 1. Collagen structures
First, a three dimensional stranded
structure is assembled, with the amino acids glycine and proline as its
principal components. This is not yet collagen but its precursor, procollagen.
A recent study shows that vitamin C must have an important role in its
synthesis. Prolonged exposure of cultures of human connective-tissue cells to
ascorbate induced an eight-fold increase in the synthesis of collagen with no
increase in the rate of synthesis of other proteins. Since the production of
procollagen must precede the production of collagen, vitamin C must have a role
in this step. The conversion involves a reaction that substitutes a hydroxyl
group, OH, for a hydrogen atom, H, in the proline residues at certain points in
the polypeptide chains, converting those residues to hydroxyproline. This
hydroxylation reaction organizes the chains in the conformation necessary for
them to form a triple helix. The hydroxylation, next, of the residues of the
amino acid lysine, transforming them to hydroxylysine, is then needed to permit
the cross-linking of the triple helices into the fibers and networks of the
tissues.
These hydroxylation reactions are
catalyzed by two different enzymes: prolyl-4-hydroxylase and lysyl-hydroxylase.
Vitamin C also serves with them in inducing these reactions. in this service,
one molecule of vitamin C is destroyed for each H replaced by OH. The synthesis
of collagen occurs inside and outside of the cell. The formation of collagen
which results in fibrillary collagen (most common form) is discussed here.
Meshwork collagen, which is often involved in the formation of filtration
systems is the other form of collagen. It should be noted that all types of
collagens are triple helixes, and the differences lie in the make-up of the
alpha peptides created in step 2.
1.
Transcription of
mRNA: There are approximately 34 genes
associated with collagen formation, each coding for a specific mRNA sequence,
and typically have the "COL" prefix. The beginning of collagen
synthesis begins with turning on genes which are associated with the formation
of a particular alpha peptide (typically alpha 1, 2 or 3).
2.
Pre-pro-peptide
Formation: Once the final mRNA exits from the
cell nucleus and enters into the cytoplasm it links with the ribosomal subunits
and the process of translation occurs. The early/first part of the new peptide
is known as the signal sequence. The signal sequence on the N-terminal
of the peptide is recognized by a signal recognition particle on the
endoplasmic reticulum, which will be responsible for directing the
pre-pro-peptide into the endoplasmic reticulum. Therefore, once the synthesis
of new peptide is finished, it goes directly into the endoplasmic reticulum for
post-translational processing. Note that it is now known as pre-pro-collagen.
Fig. Biosynthesis of collagen from
Preprocollagen
3.
Alpha Peptide to
Procollagen: Three modifications of the
pre-pro-peptide occur leading to the formation of the alpha peptide. Secondly,
the triple helix known as procollagen is formed before being transported in a
transport vesicle to the golgi apparatus. 1) The signal peptide on the
N-terminal is dissolved, and the molecule is now known as propeptide
(not procollagen). 2) Hydroxylation of lysines and prolines on propeptide by the
enzymes prolyl hydroxylase and lysyl hydroxylase (to produce
hydroxyproline and hydroxylysine) occurs to aid crosslinking of the alpha
peptides. It is this enzymatic step that requires vitamin C as a cofactor. In scurvy,
the lack of hydroxylation of prolines and lysines causes a looser triple helix
(which is formed by 3 alpha peptides). 3) Glycosylation occurs by adding either
glucose or galactose monomers onto the hydroxy groups that were placed onto
lysines, but not on prolines. From here the hydroxylated and glycosylated
propeptide twists towards the left very tightly and then three propeptides will
form a triple helix. It is important to remember that this molecule, now known
as procollagen (not propeptide) is composed of a twisted portion
(center) and two loose ends on either end. At this point the procollagen is
packaged into a transfer vesicle destined for the golgi apparatus.
4.
Golgi Apparatus
Modification: In the golgi apparatus, the
procollagen goes through one last post-translational modification before being
secreted out of the cell. In this step oligosaccharides (not monosaccharides
like in step 3) are added, and then the procollagen is packaged into a
secretory vesicle destined for the extracellular space.
5.
Formation of
Tropocollagen: Once outside the cell, membrane
bound enzymes known as collagen peptidases, remove the "loose
ends" of the procollagen molecule. What is left is known as tropocollagen.
Defect in this step produces one of the many collagenopathies known as Ehlers-Danlos syndrome. This step is
absent when synthesizing type III, a type of fibrilar collagen.
6.
Formation of the
Collagen Fibril: Lysyl oxidase an
extracellular enzyme produces the final step in the collagen synthesis pathway.
This enzyme acts on lysines and hydroxylysines producing aldehyde groups, which
will eventually undergo covalent bonding between tropocollagen molecules. This
polymer of tropocollogen is known as a collagen fibril.
Collagen has an unusual amino acid
composition and sequence:
·
Glycine
is found at almost every third residue
·
Proline
(Pro) makes up about 17% of collagen
·
Collagen contains
two uncommon derivative amino acids not directly inserted during translation. These amino acids are found
at specific locations relative to glycine and are modified post-translationally
by different enzymes, both of which require vitamin C
as a cofactor.
o Hydroxyproline (Hyp), derived from proline.
o Hydroxylysine (Hyl), derived from lysine (Lys).
Depending on the type of collagen, varying numbers of hydroxylysines are glycosylated
(mostly having disaccharides attached).
Cortisol
stimulates degradation of (skin) collagen into amino
acids.
Most collagen forms in a similar
manner, but the following process is typical for type I:
1.
Inside the cell
1.
Two types of peptide
chains are formed during translation on ribosomes along the rough endoplasmic reticulum (RER): alpha-1
and alpha-2 chains. These peptide chains (known as preprocollagen) have registration peptides on
each end and a signal peptide.
2.
Polypeptide chains
are released into the lumen of the RER.
3.
Signal peptides are
cleaved inside the RER and the chains are now known as pro-alpha chains.
4.
Hydroxylation
of lysine
and proline
amino acids occurs inside the lumen. This process is dependent on ascorbic acid
(Vitamin C) as a cofactor.
5.
Glycosylation
of specific hydroxylysine residues occurs.
6.
Triple ɣ helical structure is formed inside
the endoplasmic reticulum from each two alpha-1 chains and one alpha-2 chain.
7.
Procollagen
is shipped to the Golgi apparatus, where it is packaged and
secreted by exocytosis.
2.
Outside the cell
1.
Registration
peptides are cleaved and tropocollagen is formed by procollagen peptidase.
2.
Multiple
tropocollagen molecules form collagen fibrils, via covalent cross-linking (aldol
reaction) by lysyl oxidase which links hydroxylysine and
lysine residues. Multiple collagen fibrils form into collagen fibers.
3.
Collagen may be
attached to cell membranes via several types of protein, including fibronectin
and integrin.
Vitamin C deficiency
causes scurvy,
a serious and painful disease in which defective collagen prevents the formation of
strong connective tissue. Gums
deteriorate and bleed, with loss of teeth; skin discolors, and wounds do not heal. Prior
to the eighteenth century, this condition was notorious among long duration
military, particularly naval, expeditions during which participants were
deprived of foods containing Vitamin C.
An autoimmune disease such as lupus erythematosus or rheumatoid arthritis may attack healthy
collagen fibers.
Many bacteria and
viruses have virulence factors which destroy collagen (such as the enzyme
collagenase) or interfere with its production.
The tropocollagen or collagen
molecule is a subunit of larger collagen aggregates such as fibrils. At
approximately 300 nm long and 1.5 nm in diameter, it is made up of
three polypeptide
strands (called alpha peptides, see step 2), each possessing the conformation
of a left-handed helix
(its name is not to be confused with the commonly occurring alpha helix, a
right-handed structure). These three left-handed helices are twisted together
into a right-handed coiled coil, a triple helix or "super
helix", a cooperative quaternary structure stabilized by
numerous hydrogen bonds. With type I collagen and
possibly all fibrillar collagens if not all collagens, each triple-helix
associates into a right-handed super-super-coil referred to as the collagen
microfibril. Each microfibril is interdigitated with its neighboring
microfibrils to a degree that might suggest they are individually unstable,
although within collagen fibrils, they are so well ordered as to be
crystalline.
A distinctive feature of collagen is
the regular arrangement of amino acids in each of the three chains of
these collagen subunits. The sequence often follows the pattern Gly-Pro-X
or Gly-X-Hyp, where X may be any of various other amino
acid residues. Proline or hydroxyproline constitute about 1/6 of the total
sequence. With glycine accounting for the 1/3 of the sequence, this means
approximately half of the collagen sequence is not glycine, proline or
hydroxyproline, a fact often missed due to the distraction of the unusual GX1X2
character of collagen alpha-peptides. The high glycine content of collagen is
important with respect to stabilization of the collagen helix as this allows
the very close association of the collagen fibers within the molecule,
facilitating hydrogen bonding and the formation of intermolecular cross-links.
This kind of regular repetition and high glycine content is found in only a few
other fibrous proteins, such as silk fibroin. About 75-80% of silk is (approximately)
-Gly-Ala-Gly-Ala- with 10% serine, and elastin is rich in glycine, proline, and
alanine (Ala), whose side group is a small methyl group.
Such high glycine and regular repetitions are never found in globular proteins
save for very short sections of their sequence. Chemically
reactive side groups are not needed in structural proteins, as they
are in enzymes and transport proteins; however, collagen is
not quite just a structural protein. Due to its key role in the determination
of cell phenotype, cell adhesion, tissue regulation and infrastructure, many
sections of its nonproline-rich regions have cell or matrix association /
regulation roles. The relatively high content of proline and hydroxyproline
rings, with their geometrically constrained carboxyl
and (secondary) amino
groups, along with the rich abundance of glycine, accounts for the tendency of
the individual polypeptide strands to form left-handed helices spontaneously,
without any intrachain hydrogen bonding.
Because glycine is the smallest amino
acid with no side chain, it plays a unique role in fibrous structural proteins.
In collagen, Gly is required at every third position because the assembly of
the triple helix puts this residue at the interior (axis) of the helix, where
there is no space for a larger side group than glycine’s single hydrogen atom.
For the same reason, the rings of the Pro and Hyp must point outward. These two
amino acids help stabilize the triple helix—Hyp even more so than Pro; a lower
concentration of them is required in animals such as fish, whose body
temperatures are lower than most warm-blooded animals. Lower proline
and hydroxyproline contents are characteristic of cold-water, but not
warm-water fish; the latter tend to have similar proline and hydroxyproline contents
to mammals. The lower proline and hydroxproline contents of cold-water fish and
other poikilotherm animals leads to their collagen
having a lower thermal stability than mammalian collagen. This lower thermal
stability means that gelatin derived from fish collagen is not suitable for many
food and industrial applications.
The tropocollagen subunits
spontaneously self-assemble, with regularly staggered
ends, into even larger arrays in the extracellular
spaces of tissues. In the fibrillar collagens, the molecules are staggered from
each other by about 67 nm (a unit that is referred to as ‘D’ and changes depending
upon the hydration state of the aggregate). Each D-period contains four plus a
fraction collagen molecules, because 300 nm divided by 67 nm does not
give an integer (the length of the collagen molecule divided by the stagger
distance D). Therefore, in each D-period repeat of the microfibril, there is a
part containing five molecules in cross-section, called the “overlap”, and a
part containing only four molecules, called the "gap". The
triple-helices are also arranged in a hexagonal or quasihexagonal array in
cross-section, in both the gap and overlap regions.
There is some covalent
crosslinking within the triple helices, and a variable amount of covalent
crosslinking between tropocollagen helices forming well organized aggregates
(such as fibrils). Larger fibrillar bundles are formed with the aid of several
different classes of proteins (including different collagen types),
glycoproteins and proteoglycans to form the different types of mature tissues
from alternate combinations of the same key players. Collagen's insolubility
was a barrier to the study of monomeric collagen until it was found that
tropocollagen from young animals can be extracted because it is not yet fully crosslinked.
However, advances in microscopy techniques (i.e. electron microscopy (EM) and
atomic force microscopy (AFM)) and X-ray diffraction have enabled researchers
to obtain increasingly detailed images of collagen structure in situ. These later advances are
particularly important to better understanding the way in which collagen
structure affects cell-cell and cell-matrix communication, and how tissues are
constructed in growth and repair, and changed in development and disease. For
example using AFM –based nanoindentation it has been shown that a single
collagen fibril is a heterogeneous material along its axial direction with
significantly different mechanical properties in its gap and overlap regions,
correlating with its different molecular organizations in these two regions.
Collagen
fibrils are semicrystalline aggregates of collagen
molecules. Collagen fibers are bundles of fibrils.
Collagen fibrils/aggregates are
arranged in different combinations and concentrations in various tissues to
provide varying tissue properties. In bone, entire collagen triple helices lie
in a parallel, staggered array. 40 nm gaps between the ends of the
tropocollagen subunits (approximately equal to the gap region) probably serve
as nucleation sites for the deposition of long, hard, fine crystals of the
mineral component, which is (approximately) Ca10(OH)2(PO4)6.
Type I collagen gives bone its tensile
strength.
Collagen occurs in many places
throughout the body. Over 90% of the collagen in the body, however, is of type
I.
So far, 28 types of
collagen have been identified and described. The five most common types are:
·
Collagen I: skin,
tendon, vascular ligature, organs, bone (main component of the organic part of
bone)
·
Collagen II: cartilage
(main component of cartilage)
·
Collagen III:
reticulate (main component of reticular
fibers), commonly found alongside type I.
·
Collagen IV: forms
bases of cell basement membrane
·
Collagen V: cell
surfaces, hair and placenta
Collagen-related
diseases most commonly arise from genetic defects or nutritional deficiencies
that affect the biosynthesis, assembly, postranslational modification,
secretion, or other processes involved in normal collagen production.
Tabl. Types Of Collagen
A Number of Genetic Diseases Result From
Abnormalities in the Synthesis of Collagen
About 30 genes encode collagen, and its pathway
of biosynthesis is complex, involving at least eight enzyme-catalyzed
posttranslational steps. Thus, it is not
surprising that a number of diseases are due to mutations in collagen
genes or in genes encoding some of the enzymes involved in these
posttranslational
modifications. The diseases affecting bone (eg,
osteogenesis imperfecta) and cartilage (eg, the chondrodysplasias) will be
discussed later in this chapter.
Ehlers-Danlos syndrome comprises a group of inherited disorders whose
principal clinical features are hyperextensibility of the skin, abnormal tissue
fragility,
and increased joint mobility. The clinical picture is
variable, reflecting underlying extensive genetic heterogeneity.
At least 10 types have been recognized, most but not
all of which reflect a variety of lesions in the synthesis of collagen. Type
IV is the most serious because of its tendency for spontaneous rupture of
arteries or the bowel, reflecting abnormalities in type III collagen.
Patients with type VI, due to a deficiency of
lysyl hydroxylase, exhibit marked joint hypermobility and a tendency to ocular
rupture. A deficiency of procollagen
N-proteinase, causing formation of abnormal thin,
irregular collagen fibrils, results in type VIIC, manifested by marked
joint hypermobility and soft skin.
Alport syndrome is the designation applied to a number of genetic
disorders (both X-linked and autosomal) affecting the structure of type IV
collagen fibers, the major collagen found in the basement membranes of the
renal glomeruli (see discussion of laminin, below). Mutations in several genes
encoding type IV collagen fibers have been demonstrated. The presenting sign is
hematuria, and patients may eventually develop end-stage renal disease.
Electron microscopy reveals characteristic abnormalities of the structure of
the basement membrane and lamina densa.
In epidermolysis bullosa, the skin breaks and
blisters as a result of minor trauma. The dystrophic form is due to mutations
in COL7A1, affecting the structure of type VII collagen. This collagen
forms delicate fibrils that anchor the basal lamina to collagen fibrils in the
dermis. These anchoring fibrils have been shown to be markedly reduced in this
form of the disease, probably resulting in the blistering. Epidermolysis
bullosa simplex, another variant, is due to mutations in keratin 5.
Scurvy affects
the structure of collagen. However, it is due to a deficiency of ascorbic acid
and is not a genetic disease. Its major signs are bleeding gums, subcutaneous hemorrhages, and poor wound
healing. These signs reflect impaired synthesis of collagen due to deficiencies
of prolyl and lysyl hydroxylases, both of which require ascorbic acid as a
cofactor.
Osteoporosis - Not inherited genetically, brought on with age, associated
with reduced levels of collagen in the skin and bones, growth hormone
injections are being researched as a possible treatment to counteract any loss
of collagen.
Knobloch syndrome - Caused by a mutation in the collagen XVIII gene,
patients present with protrusion of the brain tissue and degeneration of the
retina, an individual who has family members suffering from the disorder are at
an increased risk of developing it themselves as there is a hereditary link.
Collagen is one of
the long, fibrous structural proteins whose functions are
quite different from those of globular
proteins such as enzymes. Tough bundles of collagen called collagen fibers are a major component
of the extracellular matrix that supports most
tissues and gives cells structure from the outside, but collagen is also found inside
certain cells. Collagen has great tensile
strength, and is the main component of fascia, cartilage,
ligaments,
tendons,
bone and skin. Along with
soft keratin,
it is responsible for skin strength and elasticity, and its
degradation leads to wrinkles that accompany aging. It strengthens blood vessels
and plays a role in tissue development. It is present in the cornea and lens
of the eye
in crystalline
form.
Collagen has a wide variety of applications,
from food to medical. For instance, it is used in cosmetic
surgery and burns surgery. It is widely used in the form of
collagen casings for sausages.
If collagen is sufficiently
denatured, e.g. by heating, the three tropocollagen strands separate partially
or completely into globular domains, containing a different secondary structure
to the normal collagen polyproline II (PPII), e.g. random coils.
This process describes the formation of gelatin,
which is used in many foods,
including flavored gelatin desserts. Besides food, gelatin has
been used in pharmaceutical, cosmetic, and photography industries. From a
nutritional point of view, collagen and gelatin are a poor-quality sole source
of protein since they do not contain all the essential amino acids in the proportions
that the human body requires—they are not 'complete
proteins' (as defined by food science, not that they are partially
structured). Manufacturers of collagen-based dietary supplements claim that their products
can improve skin and fingernail quality as well as joint health. However,
mainstream scientific research has not shown strong evidence to support these
claims. Individuals with problems in these areas are more likely to be
suffering from some other underlying condition (such as normal aging, dry skin,
arthritis etc.) rather than just a protein deficiency.
From the Greek for glue, kolla, the word collagen means "glue
producer" and refers to the early process of boiling the skin and sinews of horses and other animals
to obtain glue. Collagen adhesive was used by Egyptians about 4,000
years ago, and Native Americans used it
in bows
about 1,500 years ago. The oldest glue in the world, carbon-dated as more than 8,000 years old, was
found to be collagen—used as a protective lining on rope baskets and embroidered
fabrics,
and to hold utensils together; also in crisscross
decorations on human
skulls.
Collagen normally converts to gelatin, but survived due to the dry conditions.
Animal glues are thermoplastic, softening again upon reheating,
and so they are still used in making musical instruments such as fine violins and guitars, which
may have to be reopened for repairs—an application incompatible with tough, synthetic plastic
adhesives, which are permanent. Animal sinews and skins, including leather,
have been used to make useful articles for millennia.
Elastin – main protein of elastic fibrils, structure and biological role.
Elastin is a protein in connective
tissue that is elastic and allows many tissues in the
body to resume their shape after stretching or contracting. Elastin helps skin
to return to its original position when it is poked or pinched. Elastin is also
an important load-bearing tissue in the bodies of vertebrates and used in
places where mechanical energy is required to be stored. In humans, elastin is
encoded by the ELN gene.
This gene encodes a protein that is
one of the two components of elastic fibers. The encoded protein is rich in hydrophobic
amino acids such as glycine and proline, which form mobile hydrophobic regions bounded by
crosslinks between lysine
residues. Multiple transcript variants encoding different isoforms have been
found for this gene. The other name for elastin is tropoelastin. The
characterization of disorder is consistent with an entropy-driven mechanism of
elastic recoil. It is concluded that conformational disorder is a constitutive
feature of elastin structure and function.
Deletions and
mutations in this gene are associated with supravalvular aortic stenosis (SVAS) and autosomal dominant cutis laxa.
Other associated defects in elastin include Marfan's Syndrome and emphysema
caused by α1-antitrypsin deficiency.
Elastic fiber is
composed of the protein fibrillin and elastin made of simple amino acids
such as glycine,
valine,
alanine,
and proline.
The total elastin ranges from 58 to 75% of the weight of the dry defatted
artery in normal canine arteries.[6]
Comparison between fresh and digested tissues shows that, at 35% strain, a minimum
of 48% of the arterial load is carried by elastin, and a minimum of 43% of the
change in stiffness of arterial tissue is due to the change in elastin
stiffness. Elastin is made by linking many soluble tropoelastin
protein molecules, in a reaction catalyzed
by lysyl oxidase,
to make a massive insoluble, durable cross-linked
array. The amino acid responsible for these cross-links is lysine.
Tropoelastin is a specialized protein with a molecular weight of 64 to 66 kDa,
and an irregular or random coil conformation made up of 830 amino acids.
Desmosine
and isodesmosine
are types of links for the tropoelastin molecules.
Elastin serves an important function
in arteries
as a medium for pressure wave propagation to help blood flow
and is particularly abundant in large elastic blood vessels such as the aorta. Elastin is also
very important in the lungs,
elastic
ligaments, the skin, and the bladder,
elastic cartilage. It is present in all
vertebrates above the jawless fish.
Table 1 summarizes the main differences between collagen and elastin.
Table 1. Major differences between
collagen and elastin.
In contrast
to collagen, which forms fibers that are tough and have high tensile strength,
elastin is a connective tissue protein with rubber-like properties. Elastic
fibers composed of elastin and glycoprotein microfibrils are found in the
lungs, the walls of large arteries, and elastic ligaments.
They can be
stretched to several times their normal length, but recoil to their original
shape when the stretching force is relaxed.
A. Structure
of elastin
Elastin
is an insoluble protein polymer synthesized from a precursor, tropoelastin,
which is a linear polypeptide composed of about 700 amino acids that are
primarily small and nonpolar (for example, glycine, alanine, and valine).
Elastin is also rich in proline and lysine, but contains only a little
hydroxyproline and hydroxy lysine.
Tropoelastin
is secreted by the cell into the extracellular space. There it interacts with
specific glycoprotein microfibrils, such as fibrillin, which function as a
scaffold onto which tropoelastin is deposited. Some of the lysyl side chains of
the tropoelastin poly peptides are oxidatively deaminated by lysyl oxidase,
forming allysine residues. Three of the allysyl side chains plus one unaltered
lysyl side chain from the same or neighboring polypeptides form a desmosine
cross-link (Figure 4.12). This produces elastin—an extensively interconnected,
rubbery network that can stretch and bend in any direction when stressed,
giving connective tissue elasticity (Figure 4.13). Mutations in the fibrillin-1
protein are responsible for Marfan syndrome—a connective tissue disorder
characterized by impaired structural integrity in the skeleton, the eye, and
the cardiovascular system. With this disease, abnormal fibrillin protein is
incorporated into microfibrils along with normal fibrillin, inhibiting the
formation of functional microfibrils. [Note: Patients with OI, EDS, or Marfan
syndrome may have blue sclera due to tissue thinning that allows underlying
pigment to show through.]
B. Role of
1-antitrypsin in elastin degradation
1.
1-Antitrypsin: Blood and other body fluids contain a protein, α1-antitrypsin
(α1-AT,
A1AT, currently also called α1-antiproteinase), that inhibits a number of
proteolytic enzymes (also called proteases or proteinases) that hydrolyze and
destroy proteins. [Note: The inhibitor was originally named α1-antitrypsin
because it inhibits the activity of trypsin (a proteolytic enzyme synthesized
as trypsinogen by the pancreas] α1-AT comprises more than 90% of the α1-globulin
fraction of normal plasma. α1-AT has the important physiologic role of inhibiting
neutrophil elastase––a powerful protease that is released into the extracellular
space, and degrades elastin of alveolar walls, as well as other structural
proteins in a variety of tissues (Figure 4.14). Most of the α1-AT found in
plasma is synthesized and secreted by the liver. The remainder is synthesized
by several tissues, including monocytes and alveolar macrophages, which may be
important in the prevention of local tissue injury by elastase.
2. Role of
1-AT in the lungs: In the normal lung, the alveoli are
chronically exposed to low levels of neutrophil elastase released from
activated and degenerating neutrophils. This proteolytic activity can destroy
the elastin in alveolar walls if unopposed by the action of α1-AT, the
most important inhibitor of neutrophil elastase (see Figure 4.14). Because lung
tissue cannot regenerate, emphysema results from the destruction of the connective
tissue of alveolar walls.
3. Emphysema
resulting from 1-AT deficiency:
In the United
States, approximately 2–5% of patients with emphysema are predisposed to the
disease by inherited defects in α1-AT. A number of different mutations
in the gene for α1-AT
are known to cause a deficiency of this protein, but one single purine base
mutation (GAG → AAG, resulting in the substitution of lysine for glutamic
acid at position 342 of the protein) is clinically the most widespread.
The
polymerization of the mutated protein in the endoplasmic reticulum of
hepatocytes causes decreased secretion of
α1-AT by the liver. The accumulated
polymer may result in cirrhosis (scarring of the liver). In the United States,
the α1-AT
mutation is most common in Caucasians of Northern European ancestry.
An individual
must inherit two abnormal α1-AT alleles to be at risk for the development of
emphysema. In a heterozygote, with one normal and one defective gene, the
levels of α1-AT
are sufficient to protect the alveoli from damage. [Note: A specific α1-AT
methionine is required for the binding of the inhibitor to its target
proteases.
Smoking
causes the oxidation and subsequent inactivation of that methionine residue,
thereby rendering the inhibitor powerless to neutralize elastase. Smokers with α1-AT
deficiency, therefore, have a considerably elevated rate of lung destruction
and a poorer survival rate than nonsmokers with the deficiency.] The deficiency
of elastase inhibitor can be reversed by augmentation therapy—weekly intravenous
administration of α1-AT.
The α1-AT
diffuses from the blood into the lung, where it reaches therapeutic levels in
the fluid surrounding the lung epithelial cells.
§ cross-shaped
glycoprotein
§ 3
polypeptides a, b1, b2
§ carbohydrate
(13% by weight)
§ Mr
900K
§ separate
binding domains
§ collagen
IV
§ heparin
§ heparin
sulphate
§ cell
binding
§ cell
specific binding - liver, nerve
§ cell
surface receptor
§ cell
adhesion
§ migration
pathways
§ stimulates
growth of axons
§ development
and regeneration
§ differentiation
§ basal
laminae
§ most
abundant linking glycoprotein
PROTEOGLYCANS & GLYCOSAMINOGLYCANS
The
Glycosaminoglycans Found in Proteoglycans Are Built Up of Repeating
Disaccharides
Proteoglycans are proteins that contain covalently linked glycosaminoglycans.
A number of them have been characterized and given names such as syndecan,
betaglycan, serglycin, perlecan, aggrecan, versican, decorin, biglycan, and
fibromodulin. They vary in tissue distribution, nature of the core protein,
attached glycosaminoglycans, and function. The proteins bound covalently to
glycosaminoglycans are called “core proteins”; they have proved
difficult to isolate and characterize, but the use of recombinant DNA
technology is beginning to yield important information about their structures.
The amount of carbohydrate in a proteoglycan is usually much greater than is
found in a glycoprotein and may comprise up to 95% of its weight. Figures 2 and
3 show the general structure of one particular proteoglycan, aggrecan, the
major type found in cartilage.
Figure 2. Dark field electron
micrograph of a proteoglycan aggregate in which
the proteoglycan subunits and filamentous backbone are particularly well extended.
It is very large (about 2 × 103 kDa), with its
overall structure resembling that of a bottle brush. It contains a long strand
of hyaluronic acid (one type of GAG) to which link proteins are attached
noncovalently.
Figure 3. Schematic representation of the proteoglycan aggrecan.
In turn, these latter interact noncovalently with core
protein molecules from which chains of other GAGs (keratan sulfate and chondroitin
sulfate in this case) project. More details on this macromolecule are given
when cartilage is discussed below.
There are at least seven glycosaminoglycans (GAGs):
hyaluronic
acid, chondroitin sulfate, keratan sulfates
I and II, heparin, heparan sulfate, and dermatan sulfate. A GAG is an unbranched polysaccharide made
up of repeating disaccharides, one component of which is always an amino
sugar (hence the name GAG), either D-glucosamine
or D-galactosamine. The other component of the repeating disaccharide
(except in the case of keratan sulfate) is a uronic acid, either L-glucuronic
acid (GlcUA) or its 5′-epimer, L-iduronic acid (IdUA). With the
exception of hyaluronic acid, all the GAGs contain sulfate groups,
either as O-esters or as N-sulfate (in heparin and heparan sulfate).
Hyaluronic acid affords another exception because
there is no clear evidence that it is attached covalently to protein, as the
definition of a proteoglycan given above specifies. Both GAGs and proteoglycans
have proved difficult to work with, partly because of their complexity.
However, they are major components of the ground substance; they have a number
of important biologic roles; and they are involved in a number of disease
processes—so that interest in them is increasing rapidly.
Proteoglycans (mucoproteins) are formed of glycosaminoglycans (GAGs)
covalently attached to the core proteins.
They are found in
all connective tissues, extracellular matrix (ECM) and on the surfaces of many cell types.
Proteoglycans are remarkable for their diversity (different cores, different numbers of GAGs with
various lenghts and compositions).
Glycosaminoglycans forming the proteoglycans are the most abundant
heteropolisaccharides in the body. They are long unbranched molecules containing
a repeating disaccharide unit.
Usually one sugar is an uronic acid
(either D-glucuronic or L-iduronic) and the other is either GlcNAc
or GalNAc. One or both sugars contain sulfate groups (the only exception is hyaluronic acid).
GAGs are highly negatively charged what is essential for their function.
THE SPECIFIC GAGs OF PHYSIOLOGICAL
SIGNIFICANCE ARE :
Hyaluronic acid (D-glucuronate + GlcNAc)
Occurence : synovial fluid, ECM of loose connective tissue
Hyaluronic acid is unique among the GAGs because it does not contain any
sulfate and is not found covalently attached to proteins. It forms
non-covalently linked complexes with proteoglycans in the ECM. Hyaluronic acid polymers are very large (100 - 10,000 kD)
and can displace a large volume of water.
Dermatan sulfate (L-iduronate +
GlcNAc sulfate)
Occurence : skin, blood vessels, heart valves
Chondroitin sulfate (D-glucuronate +
GalNAc sulfate)
Occurence : cartilage, bone, heart valves ; It is the most abundant GAG.
Heparin and heparan sulfate (D-glucuronate
sulfate + N-sulfo-D-glucosamine)
Heparans have less sulfate groups
than heparins
Occurence :
·
Heparin :component of intracellular granules of mast cells lining
the arteries of the lungs, liver and skin.
Figure. Structure of heparin. The
polymer section illustrates structural features typical of heparin; however, the sequence of variously substituted repeating
disaccharide units has been arbitrarily selected. In addition, non-O-sulfated or 3-O-sulfated
glucosamine residues may also occur.
·
Heparan sulfate: basement membranes, component of cell surfaces.
Keratan sulfate ( Gal + GlcNAc
sulfate)
Occurence : cornea, bone, cartilage;
Keratan sulfates are often aggregated with chondroitin sulfates.
The GAGs extend perpendicular from the
core protein in a bottlebrush- like structure.
The linkage of GAGs such as (heparan
sulfates and chondroitin sulfates) to the protein core involves a specific trisaccharide linker :
Some forms of keratan sulfates
are linked to the protein core through an N-asparaginyl bond.
The protein cores of proteoglycans
are rich in Ser and Thr residues which allows multiple GAG attachment.
Proteoglycans Have Numerous
Functions
As indicated above, proteoglycans are remarkably
complex molecules and are found in every
tissue of the body, mainly in the ECM or
“ground substance.”
There they are associated with each other and also
with the other major structural components of the
matrix, collagen and elastin, in quite
specific manners. Some proteoglycans bind to collagen
and others to elastin.
These interactions are important in determining the structural organization of the matrix. Some
proteoglycans (eg, decorin) can also bind
growth factors such as TGF-â, modulating their
effects on cells. In addition, some of them interact with
certain adhesive proteins such as fibronectin and
laminin (see above), also found in the matrix. The GAGs
present in the proteoglycans are polyanions and hence
bind polycations and cations such as Na+ and K+. This
latter ability attracts water by osmotic pressure into the
extracellular matrix and contributes to its turgor. GAGs also gel
at relatively low concentrations. Because of the
long extended nature of the polysaccharide chains of GAGs
and their ability to gel, the proteoglycans can act as
sieves, restricting the passage of large macromolecules
into the ECM but allowing relatively free diffusion of
small molecules.
Again, because of their extended structures and the huge macromolecular aggregates they often form,
they occupy a large volume of the matrix relative to
proteins.
SOME FUNCTIONS OF SPECIFIC GAGS & PROTEOGLYCANS
Hyaluronic acid is especially high in
concentration in embryonic tissues and is thought
to play an important role in permitting cell migration
during morphogenesis and wound repair. Its ability to
attract water into the extracellular matrix and thereby
“loosen it up” may be important in this regard. The
high concentrations of hyaluronic acid and chondroitin
sulfates present in cartilage contribute to its
compressibility (see below).
Chondroitin sulfates are located at sites of
calcification in endochondral bone and are also
found in cartilage.
They are also located inside
certain neurons and may provide an endoskeletal
structure, helping to maintain their shape.
Both keratan sulfate I and
dermatan sulfate are present in the cornea. They
lie between collagen fibrils and play a critical role in
corneal transparency. Changes in proteoglycan composition
found in corneal scars disappear when the cornea heals. The
presence of dermatan
sulfate in the sclera may also
play a role in maintaining the overall shape of the
eye. Keratan sulfate I is also present in cartilage.
Heparin is an important anticoagulant. It binds with factors IX and XI, but its most important
interaction is with plasma antithrombin
III. Heparin can also bind specifically to lipoprotein lipase present in capillary walls, causing a release of this enzyme into the circulation.
Certain proteoglycans (eg, heparan
sulfate) are associated with the plasma membrane of
cells, with their core proteins actually spanning that
membrane. In it they may act as receptors and may
also participate in the mediation of cell growth and
cell-cell communication.
The attachment of cells to their
substratum in culture is mediated at least in part by
heparan sulfate. This proteoglycan is also found in the
basement membrane of the kidney along with type IV
collagen and laminin (see above), where it plays a
major role in determining the charge selectiveness of
glomerular filtration.
Proteoglycans are also found in
intracellular locations such as the nucleus; their
function in this organelle has not been elucidated.
They are present in some storage or secretory
granules, such as the chromaffin granules of the adrenal
medulla. It has been postulated that they play a role in
release of the contents of such granules. The various
functions of GAGs are summarized in Table 2.
Table 2. Some functions of glycosaminoglycans and proteoglycans.
ASSOCIATIONS WITH MAJOR
DISEASES & WITH AGING
Hyaluronic acid may be important in permitting tumor cells to migrate through the ECM. Tumor cells can induce fibroblasts to synthesize greatly
increased amounts of this GAG, thereby
perhaps facilitating their own spread. Some tumor cells
have less heparan sulfate at their surfaces, and this
may play a role in the lack of adhesiveness that these
cells display.
The intima of the arterial wall contains
hyaluronic acid and chondroitin sulfate,
dermatan sulfate, and heparan sulfate proteoglycans. Of
these proteoglycans, dermatan sulfate binds plasma
low-density lipoproteins.
In addition, dermatan sulfate appears to be the major GAG synthesized by arterial smooth muscle cells. Because it is these cells that proliferate
in atherosclerotic lesions in arteries, dermatan
sulfate may play an important role in development
of the atherosclerotic plaque.
In various types of arthritis, proteoglycans
may act as autoantigens, thus
contributing to the pathologic features of these
conditions. The amount of chondroitin sulfate in cartilage
diminishes with age, whereas the amounts of keratan
sulfate and hyaluronic acid increase.
These changes may contribute to the development of osteoarthritis. Changes in the amounts of
cer tain GAGs in the skin are also observed with aging and help to account for the characteristic changes
noted in this organ in the elderly.
An exciting new phase in proteoglycan research is opening up with the findings that mutations that
affect individual proteoglycans or the enzymes needed for their synthesis alter the regulation of specific
signaling pathways in drosophila and Caenorhabditis
elegans, thus affecting development; it already
seems likely that similar effects exist in mice and
humans.
EXAMPLES OF GAG BINDING PROTEINS:
Secreted proteases and antiproteases
For example antithrombin III
(AT III) binds tightly to heparin and certain heparan sulfates
(so do its substrates). Thus they control the blood coagulation. In the absence
of GAGs AT III inactivates proteases (such as thrombin, factors IXa
and XIa) very slowly. In the presence of appropriate GAGs these
reactions are accelerated 2000-fold.
GAGs are sufficiently long that both
protease and protease inhibitor can bind to the same chain (thus the likelyhood
of the two proteins binding to each other is increased enormously). GAGs also
affect the protein conformation that contributes to improving AT III binding
kinetics.
Polypeptide growth factors
Members of the FGF family, as
well as several other growth factors, bind to heparin or heparan
sulfate. Binding to endogenous GAGs entraps these molecules in ECM from
which they may be later released. GAGs can alter the conformation, proteolytic
susceptibility and biological activity of some of these proteins. The bound
growth factor is resistant to degradation by extracellular proteases. Active
hormone is released by proteolysis of the heparan sulfate chains. It occurs
during the tissue growth and remodeling after infection.
ECM proteins
Most of the large, multidomain ECM
proteins contain at least one GAG binding site.
For example fibrous collagens
(type I, III, V) and fibronectin bind to heparan sulfate chains
which are attached to the integral membrane core proteins of cell surface
proteoglycans such as syndecan and fibroglycan. Cell surface
proteoglycans are thought to anchor cells to matrix fibers.
Cell-cell adhesion molecules
·
For example NCAM
(see cadherins) interacts with cell surface
heparan sulfate proteoglycans. This interaction is required for its
function. NCAM has a distinct heparan binding domain.
·
Hyaluronan is bound to the surface receptors (e.g. CD44) of
many migrating cells. It is very important during differentiation (for example myoblasts
which are undifferentiated muscle cell precursors bear hyaluronan- rich coat
that prevents premature cell fusion). Because its loose, hydrated porous
structure, the hyaluronan coat keeps cells apart from each other. They are free
to move around and proliferate.
When the
level of hyaluronan is lower (e.g. because of digesting by hyaluronidase),
there is ceesation of cell movement and initiation of cell- cell attachment.
Mucopolysaccharidoses and collagenoses, their
biochemical diagnostics
Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or
malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans - long chains of sugar carbohydrates
in each of our cells that help build bone, cartilage,
tendons,
corneas,
skin and connective
tissue. Glycosaminoglycans (formerly called mucopolysaccharides) are
also found in the fluid that lubricates our joints.
People with a mucopolysaccharidosis
disease either do not produce enough of one of the 11 enzymes required to break
down these sugar chains into simpler molecules, or they produce enzymes that do
not work properly. Over time, these glycosaminoglycans collect in the cells,
blood and connective tissues. The result is permanent, progressive cellular
damage which affects appearance, physical abilities, organ and system
functioning, and, in most cases, mental development.
The mucopolysaccharidoses are part of
the lysosomal storage disease family, a group
of more than 40 genetic disorders that result when a specific organelle in our
body's cells – the lysosome – malfunctions. The lysosome is commonly referred
to as the cell’s recycling center because it processes unwanted material into
substances that the cell can utilize. Lysosomes break down this unwanted matter
via enzymes, highly specialized proteins essential for survival. Lysosomal
disorders like mucopolysaccharidosis are triggered when a particular enzyme
exists in too small an amount or is missing altogether.
The mucopolysaccharidoses share many
clinical features but have varying degrees of severity. These features may not
be apparent at birth but progress as storage of glycosaminoglycans affects
bone, skeletal structure, connective tissues, and organs. Neurological
complications may include damage to neurons (which
send and receive signals throughout the body) as well as pain and impaired motor
function. This results from compression of nerves or nerve
roots in the spinal cord or in the peripheral nervous system, the part of the
nervous
system that connects the brain and spinal cord to sensory organs such as the eyes
and to other organs, muscles, and tissues throughout the body.
Depending on the
mucopolysaccharidosis subtype, affected individuals may have normal intellect
or have cognitive impairments, may experience developmental delay, or may have
severe behavioral problems. Many individuals have hearing loss, either
conductive (in which pressure behind the ear drum causes fluid from the lining
of the middle ear to build up and eventually congeal), neurosensitive (in which
tiny hair cells in the inner ear are damaged), or both. Communicating
hydrocephalus — in which the normal reabsorption of cerebrospinal fluid is
blocked and causes increased pressure inside the head — is common in some of
the mucopolysaccharidoses. Surgically inserting a shunt
into the brain can drain fluid. The eye's cornea often
becomes cloudy from intracellular storage, and glaucoma
and degeneration of the retina also may affect the patient's vision.
Physical symptoms generally include
coarse or rough facial features (including a flat nasal bridge, thick lips, and
enlarged mouth and tongue), short stature with disproportionately short trunk (dwarfism),
dysplasia
(abnormal bone size and/or shape) and other skeletal irregularities, thickened
skin, enlarged organs such as liver (hepatomegaly)
or spleen (splenomegaly), hernias,
and excessive body hair growth. Short and often claw-like hands, progressive
joint stiffness, and carpal tunnel syndrome can restrict hand
mobility and function. Recurring respiratory infections are common, as are
obstructive airway disease and obstructive sleep apnea.
Many affected individuals also have heart disease, often involving enlarged or
diseased heart valves.
Another lysosomal storage disease
often confused with the mucopolysaccharidoses is mucolipidosis.
In this disorder, excessive amounts of fatty materials known as lipids (another
principal component of living cells) are stored, in addition to sugars. Persons
with mucolipidosis may share some of the clinical features associated with the
mucopolysaccharidoses (certain facial features, bony structure abnormalities,
and damage to the brain), and increased amounts of the enzymes needed to break
down the lipids are found in the blood.
Seven distinct clinical types and
numerous subtypes of the mucopolysaccharidoses have been identified. Although
each mucopolysaccharidosis (MPS) differs clinically, most patients generally
experience a period of normal development followed by a decline in physical
and/or mental function.
Diagnosis often can
be made through clinical examination and urine tests (excess
mucopolysaccharides are excreted in the urine). Enzyme assays (testing a
variety of cells or body fluids in culture for enzyme deficiency) are also used
to provide definitive diagnosis of one of the mucopolysaccharidoses. Prenatal
diagnosis using amniocentesis and chorionic villus sampling can verify if a
fetus either carries a copy of the defective gene or is affected with the
disorder. Genetic counseling can help parents who have a family history of the
mucopolysaccharidoses determine if they are carrying the mutated gene that
causes the disorders.
Any of various diseases or abnormal states (as rheumatoid
arthritis, systemic lupus erythematosus, polyarteritis nodosa, rheumatic fever,
and dermatomyositis) characterized by inflammatory or degenerative changes in
connective tissue—called also collagen
disease, collagenolysis, collagen vascular disease
• The major components of the ECM are the
structural proteins collagen, elastin, and fibrillin; a number of specialized
proteins (eg, fibronectin and laminin); and various proteoglycans.
• Collagen is the most abundant protein in the animal
kingdom; approximately 19 types have been isolated.
• Collagen and elastin are fibrous proteins.
Collagen molecules contain an abundance of proline, lysine, and glycine, the
latter occurring at every third position in the primary structure. Collagen
also contains hydroxyproline, hydroxylysine, and glycosylated hydroxylysine,
each formed by posttranslational modification.
• Collagen molecules typically form fibrils
containing a long, stiff, triple-stranded helical structure, in which three
collagen polypeptide chains are wound around one another in a rope-like
superhelix (triple helix). Other types of collagen form mesh-like networks.
All collagens contain greater or lesser stretches
of triple helix and the repeating structure (Gly-X-Y)n.
• The biosynthesis of collagen is complex,
featuring many posttranslational events, including hydroxylation of proline and
lysine.
• Diseases associated with impaired synthesis of
collagen include scurvy, osteogenesis imperfecta, Ehlers-Danlos syndrome (many
types), and Menkes disease.
• Elastin confers extensibility and elastic
recoil on tissues.
• Elastin lacks hydroxylysine, Gly-X-Y sequences,
triple helical structure, and sugars but contains desmosine and isodesmosine
cross-links not found in collagen.
• Elastin is a connective tissue protein with
rubber-like properties in tissues such as the lung. 1-Antitrypsin (α1-AT),
produced primarily by the liver but also by tissues such as monocytes and
alveolar macrophages, prevents elastin degradation in the alveolar walls. A
deficiency of α1-AT can cause emphysema and, in some cases, cirrhosis of
the liver.
• Fibrillin is located in microfibrils. Mutations
in the gene for fibrillin cause Marfan syndrome.
• The glycosaminoglycans (GAGs) are made up of
repeating disaccharides containing a uronic acid (glucuronic or iduronic) or
hexose (galactose) and a hexosamine (galactosamine or glucosamine). Sulfate is
also frequently present.
• The major GAGs are hyaluronic acid, chondroitin
4- and 6-sulfates, keratan sulfates I and II, heparin, heparan sulfate, and
dermatan sulfate.
• The GAGs are synthesized by the sequential
actions of a battery of specific enzymes (glycosyltransferases, epimerases,
sulfotransferases, etc) and are degraded by the sequential action of lysosomal
hydrolases. Genetic deficiencies of the latter result in mucopolysaccharidoses
(eg, Hurler syndrome).
• GAGs occur in tissues bound to various proteins
(linker proteins and core proteins), constituting proteoglycans.
These structures are often of very high molecular
weight and serve many functions in tissues.
• Many components of the ECM bind to proteins of
the cell surface named integrins; this constitutes one pathway by which the
exteriors of cells can communicate with their interiors.
• Bone and cartilage are specialized forms of the
ECM.
Collagen I and hydroxyapatite are the major
constituents of bone. Collagen II and certain proteoglycans are major
constituents of cartilage.