Modifications of glycans: biological significance and therapeutic opportunities

Abstract

Carbohydrates play a central role in a wide range of biological processes. As with nucleic acids and proteins, modifications of specific sites within the glycan chain can modulate a carbohydrate's overall biological function. For example, acylation, methylation, sulfation, epimerization, and phosphorylation can occur at various positions within a carbohydrate to modulate bioactivity. Therefore, there is significant interest in identifying discrete carbohydrate modifications and understanding their biological effects. Additionally, enzymes that catalyze those modifications and proteins that bind modified glycans provide numerous targets for therapeutic intervention. This review will focus on modifications of glycans that occur after the oligomer/polymer has been assembled, generally referred to as post-glycosylational modifications.

Figure 1

Representative examples of common carbohydrate modifications in nature. Symbols for each monosaccharide component are identified in the legend. Glycosidic linkages are identified by α or β with a number that identifies the carbon atom of the acceptor sugar. O-Acetylation is indicated by Ac, O-phosphorylation is indicated by P, O-methylation is indicated by Me, N-sulfation is indicated by NS, O-sulfation is indicated by S,O-ferulyl is indicated by Fr, and the numbers indicate the carbon atom where the modification occur on the monosaccharide. (a) Structure of 9-O-acetylated sialyl Lewis X. (b) Structure diversity of sialic acids. (c) Alginate structure from P. aeruginosa. (d) Mannose-6-phosphate (Man 5). (e) Structure of sulfatide. (f) β1,2–D-Xylopyranosyl-5-O-trans-ferulyl-L-arabinofuranose (FAX). (g) O-Methylated glycan from gastropods. (h) Structure of heparin pentasaccharide.

Figure 2

Medical significance of modified glycans. (a) Modified glycans mediate biological functions across various organ systems, and they have been linked to malignant, degenerative, infectious, and inflammatory diseases. (b) Strategies that intervene in these functions could lead to new classes of therapies. Production of modified glycans can be downregulated by targeting their biosynthetic machinery, either by blocking expression or activity of carbohydrate modifying enzymes. Antibodies and glycomimetics can disrupt the ligand-receptor interactions of modified glycans. Finally, therapeutic strategies can target the extracellular esterases that remodel patterns of glycan modifications.

Figure 3

Biosynthesis and structures of sulfated GAGs. A family of carbohydrate sulfotransferases catalyzes the sulfation of GAGs at specific positions within the repeating disaccharide repeat units.

Figure 4

Sulfation tunes biological activity of GAGs. Sulfates are not uniformly positioned along the GAG backbone. Cells modulate the linkage and density of sulfates added to the GAG core as one way of regulating a sulfated GAG’s biological function. Ligands that bind to sulfated GAGs recognize specific patterns of sulfation, sometimes referred to as the “sulfation code”. In this example, the sulfation pattern of heparan sulfate determines the binding affinity for cytokines and growth factors. Some regions, known as S-domains, are heavily sulfated and have high affinity for ligands. Other regions contain fewer or no sulfates.