Histories of Dermatan Sulfate Epimerase and Dermatan 4-O-Sulfotransferase from Discovery of Their Enzymes and Genes to Musculocontractural Ehlers-Danlos Syndrome

Abstract

Dermatan sulfate (DS) and its proteoglycans are essential for the assembly of the extracellular matrix and cell signaling. Various transporters and biosynthetic enzymes for nucleotide sugars, glycosyltransferases, epimerase, and sulfotransferases, are involved in the biosynthesis of DS. Among these enzymes, dermatan sulfate epimerase (DSE) and dermatan 4-O-sulfotranserase (D4ST) are rate-limiting factors of DS biosynthesis. Pathogenic variants in human genes encoding DSE and D4ST cause the musculocontractural type of Ehlers-Danlos syndrome, characterized by tissue fragility, joint hypermobility, and skin hyperextensibility. DS-deficient mice exhibit perinatal lethality, myopathy-related phenotypes, thoracic kyphosis, vascular abnormalities, and skin fragility. These findings indicate that DS is essential for tissue development as well as homeostasis. This review focuses on the histories of DSE as well as D4ST, and their knockout mice as well as human congenital disorders.

A biological guide to glycosaminoglycans: current perspectives and pending questions

“…Polymerization of the CS backbone in the endoplasmic reticulum (ER)/Golgi complex. The transfer of GalNAc to the nonreducing terminal GlcA residue of the tetrasaccharide linker is catalyzed by β1,4‐ N ‐acetylgalactosaminyltransferase‐I (GalNAcT‐I) encoded by the chondroitin sulfate N ‐acetylgalactosaminyltransferase CSGALNACT1 and CSGALNACT2 genes [37]. The addition of this residue triggers chondroitin sulfate CS polymerization [38].…”

“…Dermatan 4‐sulfotransferase (D4ST) catalyzes the sulfation of C4 in GalNAc residues leading to the formation of IdoA‐GalNAc4S‐rich clusters in DS chains. DSE‐1, in contrast with DSE‐2, can form a complex with D4ST, which is required to synthesize longer IdoA‐containing chains [37]. The importance of the position of sulfate groups and the epimerization of GlcA residues is supported by the findings that the structure, conformation, and dynamics of CS4, CS6, and DS analyzed by molecular dynamics differ [42].…”

“…The importance of the position of sulfate groups and the epimerization of GlcA residues is supported by the findings that the structure, conformation, and dynamics of CS4, CS6, and DS analyzed by molecular dynamics differ [42]. The 4‐sulfation of GlcA residue by dermatan 4‐ O ‐sulfotransferase 1 (D4ST1) is required to stabilize epimerization [37,43]. The CS/DS ratio is critical for the development of many tissues [44].…”