Intracellular Post-Translational Modifications of Collagens

Abstract

Collagen synthesis involves many post-translational modifications, the collagen-specific intracellular modifications consisting of hydroxylation of certain proline and lysine residues to 4-hydroxyproline, 3-hydroxyproline and hydroxylysine, and glycosylation of some of the hydroxylysine residues to galactosylhydroxylysine and glucosylgalactosylhydroxylysine. The five enzymes catalyzing these modifications are collagen prolyl 4-hydroxylase, prolyl 3-hydroxylase, lysyl hydroxylase, collagen galactosyltransferase and collagen glucosyltransferase, all residing within the lumen of the endoplasmic reticulum. Vertebrate collagen prolyl 4-hydroxylase, prolyl 3-hydroxylase and lysyl hydroxylase have at least three isoenzymes, and all collagen hydroxylases belong to the group of 2-oxoglutarate dioxygenases, which require Fe²⁺, 2-oxoglutarate, O₂ and ascorbate. Although the three-dimensional structures of these enzymes are still unknown, detailed information is available on their catalytically critical residues and reaction mechanisms. 4-Hydroxyproline residues have an essential role in providing the collagen triple helices with thermal stability, and collagen prolyl 4-hydroxylase is therefore regarded as an attractive target for chemical inhibition to control excessive collagen accumulation, e.g. in fibrotic diseases and cases of severe scarring.