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Fluorinated sugars as probes of glycosidase mechanisms

TitleFluorinated sugars as probes of glycosidase mechanisms
Publication TypeConference Paper
Year of Publication1996
AuthorsNAMCHUK, M, BRAUN, C, MCCARTER, JD, Withers, SG
EditorOjima, I, , , Welch, JT
Conference NameBIOMEDICAL FRONTIERS OF FLUORINE CHEMISTRY
PublisherAmer Chem Soc, Div Fluorine Chem; Amer Chem Soc, Div Medicinal Chem
ISBN Number0-8412-3442-6
Abstract

Fluorinated sugars have proved to be valuable mechanistic probes of glycosidases in several ways. This is illustrated forAgrobacterium beta-glucosidase, a retaining glycosidase which hydrolyses glycosidic bonds with net retention of anomeric configuration via a double displacement mechanism involving a glycosyl-enzyme intermediate. Both ground state and transition state interactions with the individual hydroxyl groups have been probed by use of a series of deoxy- and deoxyfluoroglycosides revealing the importance of interactions at the 2-position. Two <(new)under bar> approaches to the trapping of the glycosyl-enzyme intermediate are now described. Incorporation of two fluorines at C-2 slows both the glycosylation and deglycosylation steps enormously, and allows the incorporation of an exceptionally good leaving group at the anomeric centre without undue lability. Thus the 2,4,6-trinitrophenyl alpha-D-2-deoxy-2,2-difluoro arabino and malto glycosides are time-dependent inactivators of yeast alpha-glucosidase and human pancreatic alpha-amylase, respectively. Alternatively, installation of a single fluorine at C-5 along with a fluoride leaving group at the anomeric centre provides a novel class of mechanism-based inactivators of both alpha- and beta-glycosidases, and has allowed identification of the active site nucleophile in yeast alpha-glucosidase.