GAG subclasses

Different types of core elongation define distinct GAG subclasses. Heparan sulfates are characterized by repeats of the disaccharide GlcA(b1-4)GlcNAc(a1-4), whereas chondroitin sulfates and dermatan sulfates are formed by repeats of the disaccharide GlcA(b1-3)GalNAc(b1-4). Subsequent modifications like epimerization and sulfation take place during or after polymerization of the GAG backbone.

FIG: HS, CS, DS

The first modification of heparan sulfate chains is mediated by the GlcNAc N-deacetylase N-sulfotransferase enzyme (NDST), of which four differentially expressed isoforms exist. The next modification taking place is the C5-epimerization of GlcA, which generates iduronic acid (IdoA). The disruption of the C5-epimerase gene in mice causes neonatal lethality with defects in the skeleton, in kidneys and lungs. Finally, 3-O and 6-O sulfotransferases decorate selected residues, thus yielding complex sulfation patterns on the GAG chains. All sulfotransferases use the high-energy donor 3-phosphoadenyl-5-phosphosulfate (PAPS), which is introduced into the lumen of the Golgi apparatus by a dedicated transporter.

FIG: ELONGATION HS CHAINS

The modification of chondroitin sulfate and dermatan sulfate chains follow the same outline as heparan sulfates, but using different sulfotransferases. In fact, about 20 sulfotransferases are involved in the sulfation of GAG chains. Additional Golgi-localized sulfotransferases are active on other substrates, such as gonadotropin N-glycans, selectin ligands, glycosphingolipids (sulfatides) and on selected tyrosine residues as found in PSGL1.