Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 13, Issue 12, Pages 1911-1915Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.2c00450
Keywords
PHPT1; histidine phosphatase; covalent inhibitor; inhibition kinetics
Categories
Funding
- National Research Foundation of Korea [2019R1A2C1085154, 2020R1A6A3A13066609]
- National Research Foundation of Korea [2020R1A6A3A13066609, 2019R1A2C1085154] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Despite the recent discovery of numerous phosphohistidine sites, their functions remain largely unknown. PHPT1 is a protein phosphatase that regulates important cellular processes, but the lack of inhibitors has hindered further research and therapeutic development.
Despite the recent discovery of numerous phosphohistidine (pHis) sites in mammalian proteomes, the functions of this labile post-translational modification (PTM) mostly remain unknown. Phosphohistidine phosphatase 1 (PHPT1), one of the few known protein pHis phosphatases, regulates important cellular processes, and its genetic knockdown attenuated cancer cell proliferation and a liver fibrosis model. Unfortunately, the lack of PHPT1 inhibitors has limited further understanding and the therapeutic potential of this unique enzyme. We report that PHPT1 can be covalently inhibited by targeting Cys73, a residue that is nonessential for the enzyme activity. We also determined the inhibition kinetics of various small molecule electrophiles as potential warheads against PHPT1. Our results lay a foundation for the development of more potent and specific PHPT1 inhibitors.
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