3.05 Biosynthesis of Glycosaminoglycans and Proteoglycans

Sulfated glycosaminoglycans (GAGs) are linear polysaccharides consisting of repeating disaccharide units composed of N-acetylhexosamine and uronic acid, and exist as proteoglycans (PGs) by attaching to specific serine residues in the core protein. PGs are ubiquitously distributed on the cell surface and in the extracellular matrix and play critical roles in a variety of physiological phenomena such as cell–cell and cell–matrix adhesion, cell proliferation, cell division, morphogenesis, and the regulation of signaling molecules via GAG chains (Figure 1). Sulfated GAGs are structurally classified into two groups, chondroitin sulfate/dermatan sulfate (CS/DS) and heparan sulfate/heparin (HS/Hep), on the basis of a difference in the repeating disaccharide unit, CS/DS and HS/Hep being composed of -4GlcAb(IdoAa)1-3GalNAcb1and -4GlcAb(IdoAa)1-4GlcNAca1-, respectively (Figure 2). These GAGs are synthesized onto a common GAG-protein linkage tetrasaccharide, GlcAb1-3Galb13Galb1-4Xylb1-O-Ser, of the core protein (Figure 3). After the synthesis of the GAG sugar backbone on this tetrasaccharide, numerous modifications including sulfation, epimerization, and desulfation are performed in a spatiotemporal manner, producing mature and functional GAG chains that exert biological functions dependent on their specific structure. Recent biochemical and molecular biological advances have led to the cloning of a series of enzymes responsible for the synthesis and modification of GAG chains, and the elucidation of their properties. Furthermore, functional analyses of GAGs using model organisms have revealed unexpected roles of these molecules. Here, we summarize the biosynthetic mechanism and the physiological functions of GAGs.