Chondroitin Sulfate Biosynthesis and Related Genes

Abstract

Chondroitin sulfate (CS) comprises repeating disaccharide units of N-acetylgalactosamine (GalNAc) and glucuronic acid (GlcA) residues with sulfate residues at different positions. CS biosynthesis (Fig. 1) is initiated by the transfer of a GalNAc residue to the linkage region of a GlcA-β1, 3-galactose (Gal)-β1, 3-Gal-β1,4-Xyl tetrasaccharide primer that is attached to a serine residue of the core protein. Then, chain elongation occurs by the alternate addition of GalNAc and GlcA residues. Enzyme activities that catalyze the initiation and elongation processes are termed as glycosyltransferase-I and II activities, respectively. To date, six glycosyltransferases involved in CS synthesis have been identified (Fig. 2): chondroitin sulfate synthase-1 (CSS-1)/chondroitin synthase (CSy) (Kitagawa et al. 2001), chondroitin sulfate synthase-2 (CSS-2)/chondroitin polymerizing factor (ChPF) (Yada et al. 2003), chondroitin sulfate synthase-3 (CSS-3), chondroitin sulfate glucuronyltransferase (CSGlcAT) (Gotoh et al. 2002a), chondroitin sulfate N-acetylgalactosaminyltransferase-1 (Gotoh et al. 2002b), and 2 (Sato et al. 2003) (CSGalNAcT-1, 2). All these enzymes have an N-terminal transmembrane domain and are localized to the Golgi apparatus where CS biosynthesis takes place. CSS-1, CSS-2, CSS-3, and CSGlcAT form a family of glycosyltransferase enzymes. CSS-1, CSS-2, and CSS-3 contain two glycosyltransferase domains and exhibit both N-acetylgalactosaminyltransferase (GalNAcT) and glucuronyltransferase (GlcAT) activities in chain elongation. Thus, they have glycosyltransferase-II (both GalNAcT-II and GlcAT-II) activity. CSGlcAT has an inactive GalNAcT domain and exhibits only GlcAT-II activity.