Collagen Synthesis

We noted in previous article that collagen is an important constituent of bone matrix. Collagen is synthesized intracellularly as swell as extracellularly.

A summary of the many steps in collagen biosynthesis is given

A. Sequence of intracellular collagen biosynthesis
1. Assembly pro-alfa chains (directed by specific mRNAs)
2. Proline hydroxylation
3. Lysine hydroxylation
4. Hydroxylysine glycosylation
5. Disulphide bond formation
6. Triple helix formation
7. Secretion

B. Sequence of extracellular collagen biosynthesis
1. Amino terminal extension cleavage
2. Carboxyl terminal extension cleavage
3. Microfibril formation
4. Lysine hydroxylysine terminal NH2 oxidation (Cu-containing lysyl oxidase)
5. Fibril formation
6. Reducible cross-link formation
7. Maturation of cross-links. Growth and reorganization of fibres

Specific enzymes are required for the hydroxylation of certain of the prolines and lysines present inn the forming collagen peptide alfa chain. These ferrous iron-containing enzymes require molecular oxygen and alfa-ketoglutarate as additional substrates, and in vitro (and probably in vivo as well) vitamin C as a cofactor.

Hydroxyproline is thus not incorporated directly into the forming collagen amino acid sequence, and free hydroxyproline will not usually be incorporated into collagen; hydroxyproline is thus a specific marker for collagen. Measurement of hydroxyproline levels provides a marker for estimation of collagen or its breakdown products. It is the introduction of hydroxyproline which leads to an amino acid sequence that can form a triple helix at normal body temperature (37 degree C).

There is fine control of collagen biosynthesis at the hydroxylation stage, as the hydroxylase cannot hydroxylate proline residues in triple helical conformation while some hydroxyp-proline is required for the triple helix to form.

Galactose and glucose are then added to some of the hydroxylysine residues, so collagen is a glycoprotein. The formation –S-S- links between the three carboxyl regions of the pro-alfa chains of a collagen molecule probably occurs before the triple helix is formed and may indeed be essential for this process to occur rapidly and efficiently in vivo. The collagen molecule is then secreted, probably via the Golgi apparatus of the forming cell.

Extracellularly, several specific proteases cleave the procollagen molecules to collagen which, in contrast to procollagen, is virtually insoluble in physiological fluids. The levels of these proteases must therefore be important in the spatial control of collagen fibril and fibre formation. The collagen molecules are then chemically cross-linked.

The chemistry of cross-linking is not yet fully understood. It is based, however, on the reaction of the lysine and hydroxylysine redidues of two collagen molecules lying side by side in a fibril. The terminal additional, amino group of one lysine residue is oxidized by a specific copper-containing amino acid oxidase to yield a reactive aldehyde grouping at the end of the lysine carbon chain.

This active group can then react with the amino group of neighbouring unoxidized lysines, to form a chemical cross-link between two collagen molecules. This link is transformed during the maturation of collagen fibres to unknown , or perhaps new peptide, bonds.

Recent evidence suggests that some cross-linking may even occur intracellularly and that collagen is secreted as packets of 10 or so procollagen molecules. In any event, the order of the various extracellular steps of collagen biosynthesis remains uncertain.

Various chemicals can prevent collagen cross-linking and thus lead to a weak connective tissue. These include the lathyrogens (beta-amino propionitrile), penicillamine and homocysteine accounting for the connecting tissue defects seen in some penicillamine treated patients or those with homocystinuria.

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Related posts:

1. Collagen In The Bone
2. Distribution of Collagens and Musculoskeletal Disorders
3. Woven Bone and Lamellar Bone
4. Non-Collagenous Proteins of Bone