D-Glucuronyl C5-Epimerase in Heparin/Heparan Sulfate Biosynthesis
Glucuronyl C5 epimerase is a key enzyme in the biosynthesis of heparin and heparan sulfate (HS), which are complex sulfated glycosaminoglycans (GAGs) composed of alternating hexuronic acid and glucosamine residues. Both species are synthesized as proteoglycans but on different core proteins (Esko 1991). Heparin is produced by connective tissue-type mast cells, whereas HS is generated by most other mammalian (and many nonmammalian) cells. The process is initiated by glycosylation reactions that generate saccharide sequences composed of alternating D-glucuronic acid (GlcA) and N-acetyl-D-glucosamine (GlcNAc) units, covalently bound to the respective core protein. The resulting polymer of (GlcAβ1,4-GlcNAcα1,4)n disaccharide repeats is modified through a series of reactions that includes N-deacetylation/N-sulfation of GlcNAc residues, C5-epimerization of the GlcA units to yield L-iduronic acid (IdoA) residues, and finally O-sulfation at various positions (Lindahl et al. 1998). The modification reactions occur in a stepwise manner, such that early steps provide the substrates for subsequent reactions. Heparin is extensively sulfated and has a high content of IdoA (typically 50%–90% of the total hexuronic acid), whereas HS has a more varied structure, generally less sulfated than heparin and with lower IdoA content (typically 30%–55% of the total hexuronic acid) (Taylor et al. 1973). The corresponding enzymes have all recently been cloned (see also Chapter 67–69, 70–72).
KeywordsHeparan Sulfate Dermatan Sulfate Heparan Sulfate Chain Hexuronic Acid Guluronic Acid
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