title: Cell-penetrant, nanomolar O-GlcNAcase inhibitors selective against lysosomal hexosaminidases.
abstract: Posttranslational modification of metazoan nucleocytoplasmic proteins with N-acetylglucosamine (O-GlcNAc) is essential, dynamic, and inducible and can compete with protein phosphorylation in signal transduction. Inhibitors of O-GlcNAcase, the enzyme removing O-GlcNAc, are useful tools for studying the role of O-GlcNAc in a range of cellular processes. We report the discovery of nanomolar OGA inhibitors that are up to 900,000-fold selective over the related lysosomal hexosaminidases. When applied at nanomolar concentrations on live cells, these cell-penetrant molecules shift the O-GlcNAc equilibrium toward hyper-O-GlcNAcylation with EC₅₀ values down to 3 nM and are thus invaluable tools for the study of O-GlcNAc cell biology.
authors.affiliation: Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee DD15EH, Scotland.
authors.forename: Helge C
authors.initials: HC
authors.lastname: Dorfmueller
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Borodkin
authors.forename: Marianne
authors.initials: M
authors.lastname: Schimpl
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zheng
authors.forename: Robert
authors.initials: R
authors.lastname: Kime
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.forename: Daan M F
authors.initials: DM
authors.lastname: van Aalten
mesh_terms: D000117:Acetylglucosamine / Q000737:chemistry; D019943:Amino Acid Substitution; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D057809:HEK293 Cells; D006596:Hexosaminidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006596:Hexosaminidases; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine