There are at least 20 distinct genes encoding the various collagen chains. The collagen genes studied thus far contain coding sequences (exons) interrupted by large, noncoding sequences (introns). The DNA is transcribed to form a precursor mRNA, which is processed to functional mRNA by excising and splicing, which remove mRNA coded by introns. The processed mRNAs leave nucleus and are transported to the polyribosomal apparatus in the rough endoplasmic reticulum for translation into polypeptide chains.
- The polypeptide chains are hydroxylated by prolyl hydroxylase and lysine hydroxylase. These enzymes require O2 Fe2+, α-ketoglutarate, and ascorbic acid (vitamin c) as cofactors. Hydroxyproline is critical to the stable formation of the triple helix. A decrease in hydroxyproline content as seen in scurvy (ascorbic acid deficiency) results in unstable molecules that lose their structures and are broken down by proteases.
- Glycosylation of hydroxylysine residues, which is important for secretion of procollagen monomers (molecules).
- Formation of interchain disulfide links, followed by procollagen triple-helix formation.
- Secretion of procollagen into the extracellular space.
- Proteolysis by procollagen peptidase of amino and carboxyl terminal telopeptides, resulting in conversion of procollagen to collagen.
- Assembly of collagen monomers (molecules) into fibrils (microfibrils) by quarter-stagger shift, followed by cross-linking of fibrils.
- End-to-end and lateral aggregation of fibrils to form collagen fiber.
Each collagen molecule is 300 nm in length and 1.5 nm in width and has five charged regions 68 nm apart. The charged regions align in a straight line when the fibrils are formed, even though the individual molecules themselves are staggered a quarter of their lengths in relation to each other. One can easily see that there are multiple steps where defects in collagen biosynthesis could result in abnormalities leading to disease.
The most important collagenolytic enzymes responsible for cleavage of type I collagen belong to the matrix metalloproteinase (MMP) group. The collagenases are secreted in latent form and, when activated, cleave the collagen molecule at a single specific site 75 percent from the amino terminal end (between residues 775-776 of α1[1] chain). Gelatinases and stromelysins degrade the unfolded fragments.
Both α-macroglobulin and tissue inhibitors of metalloproteases (TIMPs) are capable of inhibiting collagenase activity. It is likely that other collagen types have type-specific collagenases capable of degrading them. Serum procollagen peptides, urinary hydroxyproline, urinary pyridinoline/deoxypyrindinoline cross-links, and serum and urinary N-telopeptides are used as measures of collagen turnover.
