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Cell Press, Chemistry and Biology, 11(17), p. 1250-1255, 2010

DOI: 10.1016/j.chembiol.2010.09.014

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Cell-Penetrant, Nanomolar O-GlcNAcase Inhibitors Selective against Lysosomal Hexosaminidases

Journal article published in 2010 by Helge C. Dorfmueller ORCID, Vladimir S. Borodkin, Marianne Schimpl ORCID, Xiaowei Zheng, Robert Kime, Kevin D. Read, Daan M. F. van Aalten ORCID
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This paper is available in a repository.

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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.