Human Genetic Disorders and Knockout Mice Deficient in Glycosaminoglycan

Figure 3

Modification pathways of CS, DS, HS, and heparin. After formation of the GAG backbones, including chondroitin and heparan, each sugar residue is modified by sulfation, which is catalyzed at various positions by sulfotransferases, as indicated in the figure. C4ST and C6ST transfer a sulfate group from PAPS to the C-4 or C-6 position of the GalNAc residues in the CS chain, which results in the formation of A-units and C-units, respectively. Further sulfations are catalyzed by GalNAc4S-6ST or UST, which is required for the formation of disulfated disaccharide units, E-units and D-units, respectively. DS-epimerase converts GlcUA into IdoUA by epimerizing the C-5 carboxy group in the chondroitin precursor, thereby resulting in the formation of the dermatan backbone. D4ST, which is distinct from C4ST, transfers a sulfate group from PAPS to the C-4 position of the GalNAc residues in dermatan to form the iA-units. The disulfated disaccharide units, iB and iE, are infrequently synthesized by UST and GalNAc4S-6ST, which are the same enzymes as those responsible for the biosynthesis of B and E units in CS chains. Following the synthesis of the backbone of HS or heparin by HS polymerases, the first modifications, N-deacetylation and N-sulfation, are catalyzed by NDST. Some GlcUA residues are then converted to IdoUA residues by GLCE. Thereafter, the hydroxy groups at the C-2 of IdoUA and at C-3 and C-6 of N-sulfated glucosamine and/or GlcNAc are sulfated by specific sulfotransferases. The 6-O-desulfation of the N-sulfated GlcN residue in the HS and heparin chains occurs by the action of SULF in order to modify the fine structure of HS for the regulation of interactions with various signaling molecules. C4ST, chondroitin 4-O-sulfotransferase; C6ST, chondroitin 6-O-sulfotransferase; D4ST, dermatan 4-O-sulfotransferase; DSE, dermatan sulfate C5-epimerase; GalNAc4S-6ST, GalNAc 4-sulfate 6-O-sulfotransferase; GLCE, heparan sulfate C5-epimerase; HS2ST, heparan sulfate 2-O-sulfotransferase; HS3ST, heparan sulfate 3-O-sulfotransferase; HS6ST, heparan sulfate 6-O-sulfotransferase; NDST, N-deacetylase/N-sulfotransferase; UST, uronyl 2-O-sulfotransferase; NS, 2S, 4S, and 6S, 2-N-, 2-O-, 4-O-, and 6-O-sulfate, respectively.