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 journalArticle

    30 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

    Cite this

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    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.",
    keywords = "N-acetylglucosamine, Tetratricopeptide repeats, Cytosolic proteins, Insulin resistance, 3T3-L1 Adipocytes, Linked GlcNAc, Glycosylation, Nuclear, GlcNAcylation, Transferase",
    author = "Dorfmueller, {Helge C.} and Borodkin, {Vladimir S.} and Marianne Schimpl and Xiaowei Zheng and Robert Kime and Read, {Kevin D.} and {van Aalten}, {Daan M. F.}",
    year = "2010",
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    doi = "10.1016/j.chembiol.2010.09.014",
    language = "English",
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    pages = "1250--1255",
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    Cell-penetrant, nanomolar O-GlcNAcase inhibitors selective against lysosomal hexosaminidases. / Dorfmueller, Helge C.; Borodkin, Vladimir S.; Schimpl, Marianne; Zheng, Xiaowei; Kime, Robert; Read, Kevin D.; van Aalten, Daan M. F.

    In: Chemistry & Biology, Vol. 17, No. 11, 24.11.2010, p. 1250-1255.

    Research output: Contribution to journalArticle

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    AU - Borodkin, Vladimir S.

    AU - Schimpl, Marianne

    AU - Zheng, Xiaowei

    AU - Kime, Robert

    AU - Read, Kevin D.

    AU - van Aalten, Daan M. F.

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