Year: 2018
Type: article
Abstract: 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 IC50 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.
Source: Scientific Reports
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
Awards: G1514251467, Tools to enable non-specialists to model glycoconjugates and glycan-protein interactions, G2577257690, G2849562071, G3027074310, G4119906783, G4727740710, Robo4 and heparan sulfate proteoglycan in angiogenesis, Resource for Integrated Glycotechnology, G543942916, G5946456372, Genetic analysis of proteoglycan-mediated lipoprotein clearance, GENETIC CONTROL OF PROTEOGLYCAN METABOLISM, Using CRISPR-Cas9 technology to develop a mutant cell library for heparan sulfate structure-function study, G7921760796, Heparan Sulfate in Prostate Cancer, Mammalian Glycosyltransferases for use in Chemistry and Biology, G9000094507, G9000138594, G9000234891, G9000333702, G991458271
OpenAlex ID: W2886656117