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

Helge C. Dorfmueller, Vladimir S. Borodkin, Marianne Schimpl, Xiaowei Zheng, Robert Kime, Kevin D. Read, Daan M. F. van Aalten

    Research output: Contribution to journalArticlepeer-review

    38 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)1250-1255
    Number of pages6
    JournalChemistry & Biology
    Volume17
    Issue number11
    DOIs
    Publication statusPublished - 24 Nov 2010

    Keywords

    • N-acetylglucosamine
    • Tetratricopeptide repeats
    • Cytosolic proteins
    • Insulin resistance
    • 3T3-L1 Adipocytes
    • Linked GlcNAc
    • Glycosylation
    • Nuclear
    • GlcNAcylation
    • Transferase

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