Biosynthesis of collagen

Collagen is the major macromolecule of most connective
tissues. It is composed of three α chain
sub units that are wound together to form a triple
helix. Cross-linking gives the molecule a rigid and
inextensible structure. There are over 25 different α
chains that associate to yield 15 different types of collagen.
Type I collagen, which is found in large quantities
in skin and bone, comprises two α1(I)-chains and
one α2(I)-chain. The amino acid composition of collagen
is unusual among animal proteins in that it has
an abundance of proline and 4-hydroxyproline and a
few residues of 3-hydroxyproline and hydroxylysine.
The hydroxyproline residues are necessary for proper
structural conformation and stability; hydroxylysine
residues take part in cross-linking and facilitate subsequent
glycosylation and phosphorylation.
Collagen α chains are synthesized in a precursor
form known as proα chains, which have additional
non-collagenous amino acid sequences (propeptides)
at both amino and carboxyl termini. The presence of
hydroxyproline and hydroxylysine arises through the
post-translational hydroxylation of particular proline
and lysine residues in the polypeptide chain. Within
the cisternae of the rough endoplasmic reticulum,
the newly synthesized proα chains encounter three
hydroxylating enzymes. Two of these enzymes, prolyl-
4-hydroxylase and prolyl-3-hydroxylase, convert
proline residues to 4-hydroxyproline or 3-hydroxyproline
respectively, and the third, lysyl hydroxylase,
converts lysine residues to hydroxylysine. Following
amino acid modifi cation, the propeptides at the carboxyl
termini of two proα1 and one proα2 chains associate
and bond through disulphide bridges. Triple
helix formation then takes place as the protein passes
through the endoplasmic reticulum. Following attachment
of carbohydrate moieties to the carboxy
terminal propeptides, the procollagen molecules are
transported to the cell surface within secretory granules.
Enzymatic removal of the propeptides during
the process of extrusion allows the collagen molecules
to spontaneously assemble into fi brils. These are then
cross-linked by a series of covalent bonds and deposited
into the extracellular matrix.
Ascorbic acid stimulates collagen synthesis through
increased transcription of procollagen genes (Hitomi
& Tsukagoshi, 1996). Also, ascorbic acid is an essential
cofactor for the post-translational hydroxylation of
proline and lysine residues in the polypeptide chain.
Each of the enzymes concerned contains an iron ion
(maintained in the ferrous state by ascorbate) and
requires molecular oxygen and α-ketoglutarate as
co-substrates (Prockop et al., 1979) (Fig. 19.4). The
absence of wound healing is one of the features of
scurvy that can be attributed to impaired collagen
synthesis arising from lack of vitamin C.
The pathway of collagen synthesis is tightly coupled
through feedback regulation (Schwarz et al., 1987).
Proline hydroxylation stabilizes the triple helical conformation of the procollagen. This conformation
increases the secretion rates by six-fold and this in
turn leads to an increase in translational effi ciency.
Therefore ascorbate levels, solely by controlling the
activity of the proline hydroxylation step, can control
the chain of events through the whole pathway.