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Collagens
S. H. Wolbach and P. K. Howe, way back in 1926, discovered that
guinea pigs got scurvy because their furry bodies stopped producing
collagen; and when they stopped producing collagen within their
intercellular matrix. As a consequence their blood vessels lost their
structural integrity and started to leak. When citrus was put back into
the diet, their furry bodies went back to producing collagen, healed
their blood vessels, and made them healthy again.
Collagen is a very important substance in your body. Collagen is the
most abundant protein in your body. More than a third of your
body’s protein is collagen. Collagen is a structural protein that
provides the scaffolding for your body. Collagen controls the shape
of every cell in your body. Your bones and teeth are made by
trapping calcium crystals within a matrix make of collagen. Collagen
forms itself into long, white fibers that strengthen tendons and
cartilage. Collagen forms itself into sheets to protect and support
softer tissues such as the lining of your organs. When you get cut, it is
collagen that glues the tissues back together again (scare tissue is
100% collagen). Your skin is 75% collagen. Collagen is the major
connective tissue in your body; it - in essence - holds your body
together.
As important as collagen is, it actually has a fairly simple chemical
structure. It is composed of only three amino acids: glycine, proline
and lysine. The glycine and proline form polypeptide chains that twist
around each other like the strands of a rope. These strands are ‘glued’
together with cross-linkages of the amino acid lysine. This ropelike
structure makes collagen a very strong molecule with a tensile
strength greater than steel wire!
Because collagen is so pervasive in your body and so necessary for
life, your body devotes a lot of time, energy and resources to
manufacturing it in sufficient quantities. In his book, How to Live
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Longer and Feel Better, Dr. Linus Pauling called the body’s production
of collagen a ‘major manufacturing enterprise.’
Collagen gives your blood vessels their form, strength and flexibility.
Your blood vessels are made up of 3 different layers. The inner layer
is a membrane of endothelium cells (similar to skin cells) which is
held in place by a sheet of collagen. The middle layer is made of
smooth muscle held in place by a network of collagen fibers that run
lengthwise. The outer layer is made up of collagen fibers that encircle
the blood vessel. Even the smallest capillaries have a thin layer of
collagen. If they did not, the endothelium cells would have nothing to
adhere to and they would simply float away.
Collagen makes your blood vessels both strong and flexible. Because
arteries are closer to the heart than veins they need to be able to
expand and contract in rhythm with your beating heart. This
expanding and contracting is what you feel when you ‘take your
pulse’ by putting your fingers on your wrist or on the side of your
neck. What you feel is the expanding and contracting of your radial
artery (wrist) or carotid artery (neck).
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Tropocollagen triple helix
Collagen is the main protein of connective tissue in animals and the
most abundant protein in mammals, making up about 25% to 35% of
the whole-body protein content. It is naturally found exclusively in
metazoa, including sponges. In muscle tissue it serves as a major
component of endomysium. Collagen constitutes 1% to 2% of
muscle tissue, and accounts for 6% of the weight of strong,
tendinous muscles. The gelatin used in food and industry is derived
from the partial hydrolysis of collagen.
Uses
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
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component of the extra-cellular 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. It is
also used in cosmetic surgery and burns surgery. Hydrolyzed collagen
can play an important role in weight management, as a protein, it can
be advantageously used for its satiating power.
Industrial uses
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 poorquality 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
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(such as normal aging, dry skin, arthritis etc.) rather than just a
protein deficiency.
From 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, carbondated 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.
Gelatin-resorcinol-formaldehyde glue (and with formaldehyde
replaced by less-toxic pentanedial and ethanedial) has been used to
repair experimental incisions in rabbit lungs.
Medical uses
The cardiac valve rings, the central body and the cardiac skeleton of
the heart summarily represent a unique and moving collagen anchor
to the fluid mechanics of the heart. Individual valvular leaflets are
arguably held in shape by collagen under great extremes of pressure.
Calcium deposition within collagen occurs as a natural consequence
of aging. These fixed points in an otherwise static display of blood
and muscle enable current cardiac imaging technology to arrive at
ratios essentially stating blood in (Cardiac Input) and blood out
(Cardiac Output). Specified imaging such as Calcium Scoring
illustrates the utility of this methodology, especially in an aging
patient subject to pathology of the collagen underpinning.
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Collagen has been widely used in cosmetic surgery, as a healing aid
for burn patients for reconstruction of bone and a wide variety of
dental, orthopedic and surgical purposes. Some points of interest are:
1. When used cosmetically, there is a chance of allergic reactions
causing prolonged redness; however, this can be virtually
eliminated by simple and inconspicuous patch testing prior to
cosmetic use.
2. Most medical collagen is derived from young beef cattle
(bovine) from certified BSE (Bovine spongiform
encephalopathy) free animals. Most manufacturers use donor
animals from either ‘closed herds’, or from countries which
have never had a reported case of BSE such as Australia, Brazil
and New Zealand.
3. Porcine (pig) tissue is also widely used for producing collagen
sheet for a variety of surgical purposes.
4. Alternatives using the patient’s own fat, hyaluronic acid or
polyacrylamide gel are readily available.
Collagens are widely employed in the construction of artificial skin
substitutes used in the management of severe burns. These collagens
may be derived from bovine, equine or porcine, and even human,
sources and are sometimes used in combination with silicones,
glycosaminoglycans, fibroblasts, growth factors and other substances.
Collagen is also sold commercially as a joint mobility supplement.
Because proteins are broken down into amino acids before
absorption, there is no reason for orally ingested collagen to affect
connective tissue in the body, except through the effect of individual
amino acid supplementation.
Recently an alternative to animal-derived collagen has become
available. Although expensive, this human collagen, derived from
donor cadavers, placentas and aborted fetuses, may minimize the
possibility of immune reactions.
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Although it cannot be absorbed through the skin, collagen is now
being used as a main ingredient for some cosmetic makeup.
History and background
The molecular and packing structures of collagen have eluded
scientists for decades; the first evidence that it possess a regular
structure at the molecular level was presented in the mid-1930s. Since
that time many prominent scholars, including (but not limited to)
Nobel laureate Crick, and Pauling, Rich, Yonath, Brodsky, Berman
and Ramachandran concentrated on the conformation of the
collagen monomer.
Several competing models although correctly dealing with the
conformation of each individual peptide chain, gave way to the triplehelical ‘Madras’ model which provided an essentially correct model of
the molecule’s quaternary structure although this model still required
some refinement.
The packing structure of collagen has not been defined to the same
degree outside of the fibrillar collagen types, although it has been
long known to be hexagonal or quasi-hexagonal.
As with its monomeric structure, several conflicting models alleged
that either the packing arrangement of collagen molecules is ‘sheetlike’ or microfibrillar. Recently it was confirmed that the
microfibrillar structure as described by Fraser, Miller, Wess (amongst
others) was closest to the observed structure, although it oversimplified the topological progression of neighboring collagen
molecules and hence did not predict the correct conformation of the
discontinuous D-periodic pentameric arrangement termed simply: the
microfibril.
Types and associated disorders
Collagen occurs in many places throughout the body and 29 types of
collagen have thus far been identified and described in literature.
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Over 90% of the collagen in the body, however, is of type I, II, III,
and IV.
•
•
•
•
•
Collagen One: skin, tendon, vascular, ligature, organs, bone
(main component of bone)
Collagen Two: cartilage (main component of cartilage)
Collagen Three: reticulate (main component of reticular fibers),
commonly found alongside type I.
Collagen Four: forms bases of cell basement membrane
Collagen Five: Cells surfaces, hair and placenta
Collagen diseases commonly arise from genetic defects that affect the
biosynthesis, assembly, post-translational modification, secretion, or
other processes in the normal production of collagen.
Type
I
II
III
IV
Notes
Gene(s)
This is the most abundant
collagen of the human body. It is
present in scar tissue, the end
product when tissue heals by
COL1A1,
repair. It is found in tendons,
COL1A2
skin, artery walls, the
endomysium of myofibrils, fibrocartilage, and the organic part of
bones and teeth.
Hyaline cartilage, makes up 50%
of all cartilage protein. Vitreous COL2A1
humour of the eye.
This is the collagen of granulation
tissue, and is produced quickly by
young fibroblasts before the
COL3A1
tougher type I collagen is
synthesized. Reticular fiber. Also
found in artery walls, skin,
intestines and the uterus
Basal lamina; eye lens. Also serves COL4A1,
as part of the filtration system in COL4A2,
capillaries and the glomeruli of
COL4A3,
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Disorders
osteogenesis
imperfecta, EhlersDanlos Syndrome,
Infantile cortical
hyperostosis aka
Caffey's disease
Collagenopathy,
types II and XI
Ehlers-Danlos
Syndrome
Alport syndrome,
Goodpasture's
syndrome
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nephron in the kidney.
V
VI
VII
VIII
IX
X
XI
XII
XIII
XIV
XV
XVI
XVII
COL4A4,
COL4A5,
COL4A6
COL5A1,
most interstitial tissue, assoc. with
COL5A2,
type I, associated with placenta
COL5A3
COL6A1,
most interstitial tissue, associated
COL6A2,
with type I
COL6A3
forms anchoring fibrils in dermal
COL7A1
epidermal junctions
some endothelial cells
FACIT collagen, cartilage,
associated with type II and XI
fibrils
hypertrophic and mineralizing
cartilage
cartilage
COL8A1,
COL8A2
COL9A1,
COL9A2,
COL9A3
Ehlers-Danlos
syndrome (Classical)
Ulrich myopathy and
Bethlem myopathy
epidermolysis bullosa
dystrophica
Posterior
polymorphous
corneal dystrophy 2
- EDM2 and EDM3
COL11A1,
COL11A2
Schmid metaphysical
dysplasia
Collagenopathy,
types II and XI
COL10A1
FACIT collagen, interacts with
type I containing fibrils, decoring
and glycosaminoglycans
Transmembrane collagen
interacts with integrin a1b1,
fibronectin and components of
basement membranes like
nidogen and perlecan.
FACIT collagen
-
COL12A1
-
COL13A1
-
COL14A1
COL15A1
COL16A1
transmembrane collagen, also
known as BP180, a 180 kDa
protein
COL17A1
Bullous Pemphigoid
and certain forms of
junctional
epidermolysis bullosa
-
XVIII source of endostatin
XIX
FACIT collagen
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COL18A1
COL19A1
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XX
XXI
FACIT collagen
XXII XXIII MACIT collagen XXIV XXV XXVI XXVII XXVIII XXIX epidermal collagen
COL20A1
COL21A1
COL22A1
COL23A1
COL24A1
COL25A1
EMID2
COL27A1
COL28A1
COL29A1
Atopic Dermatitis
In addition to the above mentioned disorders, excessive deposition
of collagen occurs in Scleroderma ( a slowly progressive disease
marked by the deposition of fibrous connective tissues in the skin
and often in internal organs).
Amino acids
Collagen has an unusual amino acid composition and sequence:
•
•
•
Glycine (Gly) is found at almost every third residue
Proline (Pro) makes up about 9% 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, derived from lysine. Depending on the
type of collagen, varying numbers of hydroxylysines have
disaccharides attached to them.
Cortisol stimulates degradation of amino acid from skin collagen.
Synthetic pathogenesis
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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.
In the human body, a malfunction of the immune system, called an
autoimmune disease, results in an immune response in which healthy
collagen fibers are systematically destroyed with inflammation of
surrounding tissues. The resulting disease processes are called Lupus
erythematosus, and rheumatoid arthritis, or collagen tissue disorders.
Many bacteria and viruses have virulence factors which destroy
collagen or interfere with its production.
An orderly breakdown of collagen is necessary during development
and tissue remodeling. For instance, following childbirth, the uterus
reduces in size, which involves a massive degradation of collagen.
An abnormal increase in the degradation of cartilage collagen is seen
in osteoarthritis. Collagen breakdown also appears to be essential for
tumor metastases.
A number of hereditary diseases have been shown to be due to
mutations in specific collagen genes. Osteogenesis imperfecta (brittle
bone) disease is characterized by fragile bones and is due to
mutations in type I collagen.
Some cartilage disorders are caused by mutations in type II collagen.
Ruptured arteries are found in Ehlers-Danlos syndrome type IV,
which arises from mutations in type III collagen.
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