Dorfmueller Helge C, Borodkin Vladimir S, Schimpl Marianne, Zheng Xiaowei, Kime Robert, Read Kevin D, van Aalten Daan M F
Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee DD15EH, Scotland.
Chem Biol. 2010 Nov 24;17(11):1250-5. doi: 10.1016/j.chembiol.2010.09.014.
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.
后生动物核质蛋白的N-乙酰葡糖胺（O-GlcNAc）翻译后修饰是必不可少的、动态的且可诱导的，并且在信号转导中可与蛋白质磷酸化相互竞争。O-连接N-乙酰葡糖胺酶（去除O-GlcNAc的酶）的抑制剂是研究O-GlcNAc在一系列细胞过程中作用的有用工具。我们报告了纳摩尔级OGA抑制剂的发现，其对相关溶酶体己糖胺酶的选择性高达900,000倍。当以纳摩尔浓度应用于活细胞时，这些细胞穿透性分子将O-GlcNAc平衡转向高O-GlcNAcylation状态，其EC₅₀值低至3 nM，因此是研究O-GlcNAc细胞生物学的宝贵工具。
