Mutations in Biosynthetic Enzymes for the Protein Linker Region of Chondroitin/Dermatan/Heparan Sulfate Cause Skeletal and Skin Dysplasias

Figure 2

Biosynthetic assemblies of GAG-linker and GAG-disaccharide regions by various glycosyltransferases. All glycosyltransferases require a corresponding UDP-sugar, such as UDP-Xyl, UDP-Gal, UDP-GlcUA, UDP-GalNAc, and UDP-GlcNAc, as a donor substrate. After specific core proteins are synthesized, the synthesis of the common GAG-protein linker region, GlcUAβ1-3Galβ1-3Galβ1-4Xylβ1-, is initiated by XylT, which transfers a Xyl residue from UDP-Xyl to the specific serine (Ser) residue(s). The linker tetrasaccharide is subsequently produced by GalT-I, GalT-II, and GlcAT-I. These four enzymes are common to the biosynthesis of CS, DS, and HS. After the formation of the linker region, CS- and HS-polymerases assemble the chondroitin and heparan backbones, respectively. Each enzyme, its coding gene, and the corresponding inheritable disorder are aligned under the respective sugar symbols from the top of each line. CHSY, CHPF, and EXT represent chondroitin synthase, chondroitin polymerizing factor, and exostosin, respectively.