Biosynthesis of Chondroitin/Dermatan Sulfate

Abstract

SummaryChondroitin sulfate and dermatan sulfate are synthesized as galactosaminoglycan polymers containing N-acetylgalactosmine alternating with glucuronic acid. The sugar residues are sulfated to varying degrees and positions depending upon the tissue sources and varying conditions of formation. Epimerization of any of the glucuronic acid residues to iduronic acid at the polymer level constitutes the formation of dermatan sulfate. Chondroitin/dermatan glycosaminoglycans are covalently attached by a common tetrasaccharide sequence to the serine residues of core proteins while they are adherent to the inner surface of endoplasmic reticulum/Golgi vesicles. Addition of the first sugar residue, xylose, to core proteins begins in the endoplasmic reticulum, followed by the addition of two galactose residues by two distinct glycosyl transferases in the early cis/medial regions of the Golgi. The linkage tetrasaccharide is completed in the medial/trans Golgi by the addition of the first glucuronic acid residue, followed by transfer of N-acetylgalactosamine to initiate the formation of a galactosaminoglycan rather than a glucosaminoglycan. This specific N-acetylgalactosaminyl transferase is different from the chondroitin synthase involved in generation of the repeating disaccharide units to form the chondroitin polymer. Sulfation of the chondroitin polymer by specific sulfotransferases occurs as the polymer is being formed. All the enzymes in the pathway for synthesis have been cloned, with the exception of the glucuronyl to iduronyl epimerase involved in the formation of dermatan residues. IUBMB Life, 54: 177-186, 2002

Extracellular matrix in the trabecular meshwork

“…(Funderburgh 2002;Silbert and Sugumaran 2002;Sugahara and Kitagawa 2002) Studies employing several methods of identification showed that the TM expresses a number of proteoglycans (PGs) ( Table 1). This includes a number of SLRPs, CSPGs, HSPGs, and other types of PGs (Table 1).…”

Heparin and Heparan Sulfate Biosynthesis

“…Here we describe first the enzymes responsible for the synthesis of the HS repeating disaccharide region and then those for HS chain initiation in the chronological order of their discoveries. For the details of the CS/DS-synthesizing enzymes, see the article by Sugumaran and Silbert (44) in this issue.…”

Structural and Functional Characterization of Oversulfated Chondroitin Sulfate/Dermatan Sulfate Hybrid Chains from the Notochord of Hagfish

“…Chondroitin sulfate (CS) and dermatan sulfate (DS) are also found ubiquitously in the extracellular matrices and at cell surfaces, being main components of cartilage and skin, respectively. CS consists of repeating disaccharide units of -4Gl-cUA␤1-3GalNAc␤1-, whereas DS is an isomeric form of CS and is formed from precursor CS through the action of glucuronyl C5 epimerase, thus consisting of disaccharide units of -4Gl-cUA␤1-3GalNAc␤1-and -4IdoUA␣1-3GalNAc␤1-in varying proportions (2). These disaccharide units are modified during chain elongation by specific sulfotransferases at C-2 of GlcUA/ IdoUA and/or C-4 and/or C-6 of GalNAc in various combinations, producing characteristic sulfation patterns critical for binding to various functional proteins displaying enormous structural diversity, comparable with that of HS, by embedding multiple overlapping functional sequences (3).…”