Inhibition of heparan sulfate and chondroitin sulfate proteoglycan biosynthesis.
Proteoglycans (PGs) are composed of a protein moiety and a complex glycosaminoglycan (GAG) polysaccharide moiety. GAG chains are responsible for various biological activities. GAG chains are covalently attached to serine residues of the core protein. The first step in PG biosynthesis is xylosylation of certain serine residues of the core protein. A specific linker tetrasaccharide is then assembled and serves as an acceptor for elongation of GAG chains. If the production of endogenous GAG chains is selectively inhibited, one could determine the role of these endogenous molecules in physiological and developmental functions in a spatiotemporal manner. Biosynthesis of PGs is often blocked with the aid of nonspecific agents such as chlorate, a bleaching agent, and brefeldin A, a fungal metabolite, to elucidate the biological roles of GAG chains. Unfortunately, these agents are highly lethal to model organisms. Xylosides are known to prime GAG chains. Therefore, we hypothesized that modified xylose analogs may able to inhibit the biosynthesis of PGs. To test this, we synthesized a library of novel 4-deoxy-4-fluoroxylosides with various aglycones using click chemistry and examined each for its ability to inhibit heparan sulfate and chondroitin sulfate using Chinese hamster ovary cells as a model cellular system.
Garud
Dinesh R
DR
Department of Chemistry, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan.
Tran
Vy M
VM
Victor
Xylophone V
XV
Koketsu
Mamoru
M
Kuberan
Balagurunathan
B
D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology; D016466:CHO Cells; D002240:Carbohydrate Sequence; D002470:Cell Survival; D002809:Chondroitin Sulfates / Q000037:antagonists & inhibitors / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D006027:Glycosides / Q000737:chemistry; D006497:Heparan Sulfate / Q000037:antagonists & inhibitors / Q000502:physiology*; D008954:Models, Biological; D008956:Models, Chemical; D008969:Molecular Sequence Data; D011134:Polysaccharides / Q000737:chemistry; D011509:Proteoglycans / Q000737:chemistry
D020126:Brefeldin A; D002809:Chondroitin Sulfates; D006027:Glycosides; D006497:Heparan Sulfate; D011134:Polysaccharides; D011509:Proteoglycans; C010807:xylosides