Glycosaminoglycans

Glycosaminoglycans (GAG) are the largest glycans produced by animal cells and typically decorate proteins called proteoglycans. Besides their considerable length, GAG distinguish themselves by being heavily sulfated. This sulfation is reflected by the names given to GAG chains, such as heparan sulfate, chondroitin sulfate and dermatan sulfate. Proteoglycans represent a diverse family of proteins that are usually secreted in the extracellular matrix, but also found anchored to cell membranes or stored in secretory granules. Proteoglycans usually bear names with the suffix ‘can’, as for example biglycan, versican and aggrecan, but exceptions exist since decorin, aggrin and CD44 also belong to proteoglycans. The extent of GAG chains on proteoglycans varies greatly, from a single GAG chain on decorin to more than 100 chains on aggrecan. The core structure of GAG chains is unique among glycans since it features a Xyl residue b-linked to serine. The core also includes two Gal units and a GlcA unit. Although most GAG subclasses extend on this tetrasaccharide core, keratan sulfates are the exception as they elongate N-glycan and O-GalNAc cores.

FIG: GAG CORE

All glycosyltransferases and sulfotransferases involved in GAG biosynthesis are localized in the Golgi apparatus. The pathway is initiated by the two b1-O Xyl-transferase isoforms XYLT1 and XYLT2, which show broad but distinct tissue expression patterns. It is presently unknown whether the two enzymes have different substrate specificities or if they are functionally redundant. The disruption of the Xylt2 gene in mice leads to a polycystic disease reminiscent of the human polycystic kidney disease. The formation of cysts is not limited to the kidneys in Xylt2-knockout mice, but also affects the liver and the biliary tract. This phenotype indicates that decreased GAG expression impacts on the integrity of epithelial layers.

After Xyl transfer, two Gal residues are added to the core. This extension is influenced by the phosphorylation and sulfation of the core. The Golgi kinase FAM20B phosphorylates the Xyl core and thereby enhances the formation of heparan sulfate and chondroitin sulfate. By contrast the sulfotransferases involved in the modification of the GAG core are still unknown. The sulfation of the Gal residues at 4-O blocks further elongation, whereas the sulfation of the first Gal at 6-O facilitates the transfer of the second Gal residue. The transfer of b3-linked GlcA mediated by the GlcA-transferase-I enzyme (GlcAT-I) completes the biosynthesis of the GAG core. This enzyme is similar but not identical to the b1-3 GlcA-transferase GlcAT-P involved in the formation of the HNK1 epitope.