Iduronic acid in chondroitin/dermatan sulfate: biosynthesis and biological function

Abstract

The ability of chondroitin/dermatan sulfate (CS/DS) to convey biological information is enriched by the presence of iduronic acid. DS-epimerases 1 and 2 (DS-epi1 and 2), in conjunction with DS-4-O-sulfotransferase 1, are the enzymes responsible for iduronic acid biosynthesis and will be the major focus of this review. CS/DS proteoglycans (CS/DS-PGs) are ubiquitously found in connective tissues, basement membranes, and cell surfaces or are stored intracellularly. Such wide distribution reflects the variety of biological roles in which they are involved, from extracellular matrix organization to regulation of processes such as proliferation, migration, adhesion, and differentiation. They play roles in inflammation, angiogenesis, coagulation, immunity, and wound healing. Such versatility is achieved thanks to their variable composition, both in terms of protein core and the fine structure of the CS/DS chains. Excellent reviews have been published on the collective and individual functions of each CS/DS-PG. This short review presents the biosynthesis and functions of iduronic acid-containing structures, also as revealed by the analysis of the DS-epi1- and 2-deficient mouse models.

Figure 1.

Structures and biosynthetic pathways of chondroitin/dermatan sulfate (CS/DS) disaccharide units. Studies on the disaccharide composition of CS/DS chains and enzyme specificities are the basis of this scheme. In iduronic acid (IdoA)-containing units, epimerization always occurs before sulfation. In disulfated structures, 2-O-sulfation follows both 4-O and 6-O sulfation, whereas 4-O sulfation precedes 6-O sulfation when a 4S, 6-di-O–sulfated unit is generated. Dotted lines indicate putative pathways because iC and iD unit formation has not been clarified yet.

Figure 2.

Hybrid structure of chondroitin/dermatan sulfate (CS/DS) and distribution of iduronic acid (IdoA). In vivo, IdoA is commonly found in clusters (IdoA blocks) or as isolated or alternating glucuronic acid (GlcA)/IdoA residues. High expression of DS-epimerases, in close collaboration with the dermatan-specific 4-O-sulfotransferase 1 (D4ST1), is necessary for IdoA block formation.

Figure 3.

Three-dimensional structure of the DS-epi1 epimerase domain (above) and domain structure of DS-epimerases (below). A tetrasaccharide substrate is positioned in the groove formed by the two subdomains. The four N-glycosylation sites are indicated with arrows and labeled N1 to N4. The locations of signal peptides (SPs) and predicted transmembrane regions (TMs) are shown with asterisks.