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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 EC?? values down to 3 nM and are thus invaluable tools for the study of O-GlcNAc cell biology.

SUBMITTER: Dorfmueller HC

PROVIDER: S-EPMC3032886 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Cell-penetrant, nanomolar O-GlcNAcase inhibitors selective against lysosomal hexosaminidases.

Dorfmueller Helge C HC Borodkin Vladimir S VS Schimpl Marianne M Zheng Xiaowei X Kime Robert R Read Kevin D KD van Aalten Daan M F DM

Chemistry & biology 20101101 11

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 ...[more]

PMID: 21095575

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