Human Genetic Disorders and Knockout Mice Deficient in Glycosaminoglycan

Figure 2

Biosynthetic assembly of GAG backbones by various glycosyltransferases. All glycosyltransferases require a corresponding UDP-sugar, such as UDP-Xyl, -Gal, -GlcUA, -GalNAc, and -GlcNAc, as a donor substrate. After specific core proteins have been synthesized, the synthesis of the common GAG-protein linkage region, GlcUAβ1-3Galβ1-3Galβ1-4Xylβ1-, is evoked by XylT, which transfers a Xyl residue from UDP-Xyl to the specific serine (Ser) residue(s) at the GAG attachment sites. The linkage tetrasaccharide is subsequently constructed by GalT-I, GalT-II, and GlcAT-I. These four enzymes are common to the biosynthesis of CS, DS, HS, and heparin. The first β1-4-linked GalNAc residue is then transferred to the GlcUA residue in the linkage region by GalNAcT-I, which initiates the assembly of the chondroitin backbone, thereby resulting in the formation of the repeating disaccharide region, [-3GalNAcβ1-4GlcUAβ1-]_n, by CS-polymerase. Alternatively, the addition of α1-4-linked GlcNAc to the linkage region by GlcNAcT-I initiates the assembly of the repeating disaccharide region [-4GlcNAcα1-4GlcUAβ1-]_n of HS and heparin by HS-polymerase. Following the formation of the chondroitin and heparan backbones, both precursor chains are modified by sulfation and epimerization (see Figure 3). Each enzyme, its coding gene, and the corresponding inheritable disorder are described under the respective sugar symbols from the top of each line. SEMDJL1, spondyloepimetaphyseal dysplasia with joint laxity type 1.