title: N-Acetyl glycals are tight-binding and environmentally insensitive inhibitors of hexosaminidases.
abstract: Mono-, di- and trisaccharide derivatives of 1,2-unsaturated N-acetyl-d-glucal have been synthesized and shown to function as tight-binding inhibitors/slow substrates of representative hexosaminidases. Turnover is slow and not observed in the thioamide analogue, allowing determination of the 3-dimensional structure of the complex. Inhibition is insensitive to pH and to mutation of key catalytic residues, consistent with the uncharged character of the inhibitor. These properties could render this inhibitor class less prone to development of resistance.
authors.affiliation: Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T1Z3, Canada. withers@chem.ubc.ca.
authors.forename: A G
authors.initials: AG
authors.lastname: Santana
authors.forename: G
authors.initials: G
authors.lastname: Vadlamani
authors.forename: B L
authors.initials: BL
authors.lastname: Mark
authors.forename: S G
authors.initials: SG
authors.lastname: Withers
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D055162:Biocatalysis; D003847:Deoxyglucose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006596:Hexosaminidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D004791:Enzyme Inhibitors; C001289:d-glucal; D003847:Deoxyglucose; D006596:Hexosaminidases