Downstream Products are Potent Inhibitors of the Heparan Sulfate 2-O-Sulfotransferase.

Autor: Thieker DF; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, 30602, USA.; Complex Carbohydrate Research Center, University of Georgia, Athens, GA, 30602, USA., Xu Y; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Rm 1044, Genetic Medicine Building, Chapel Hill, USA., Chapla D; Complex Carbohydrate Research Center, University of Georgia, Athens, GA, 30602, USA., Nora C; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA., Qiu H; Complex Carbohydrate Research Center, University of Georgia, Athens, GA, 30602, USA., Felix T; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, 30602, USA.; Complex Carbohydrate Research Center, University of Georgia, Athens, GA, 30602, USA., Wang L; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, 30602, USA.; Complex Carbohydrate Research Center, University of Georgia, Athens, GA, 30602, USA., Moremen KW; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, 30602, USA.; Complex Carbohydrate Research Center, University of Georgia, Athens, GA, 30602, USA., Liu J; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Rm 1044, Genetic Medicine Building, Chapel Hill, USA., Esko JD; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA., Woods RJ; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, 30602, USA. rwoods@ccrc.uga.edu.; Complex Carbohydrate Research Center, University of Georgia, Athens, GA, 30602, USA. rwoods@ccrc.uga.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2018 Aug 07; Vol. 8 (1), pp. 11832. Date of Electronic Publication: 2018 Aug 07.
DOI: 10.1038/s41598-018-29602-4
Abstrakt: Heparan Sulfate (HS) is a cell signaling molecule linked to pathological processes ranging from cancer to viral entry, yet fundamental aspects of its biosynthesis remain incompletely understood. Here, the binding preferences of the uronyl 2-O-sulfotransferase (HS2ST) are examined with variably-sulfated hexasaccharides. Surprisingly, heavily sulfated oligosaccharides formed by later-acting sulfotransferases bind more tightly to HS2ST than those corresponding to its natural substrate or product. Inhibition assays also indicate that the IC 50 values correlate simply with degree of oligosaccharide sulfation. Structural analysis predicts a mode of inhibition in which 6-O-sulfate groups located on glucosamine residues present in highly-sulfated oligosaccharides occupy the canonical binding site of the nucleotide cofactor. The unexpected finding that oligosaccharides associated with later stages in HS biosynthesis inhibit HS2ST indicates that the enzyme must be separated temporally and/or spatially from downstream products during biosynthesis in vivo, and highlights a challenge for the enzymatic synthesis of lengthy HS chains in vitro.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje