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Identification of a Target Site for Covalent Inhibition of Protein Phosphohistidine Phosphatase 1.

ABSTRACT: 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.

SUBMITTER: Kim HJ

PROVIDER: S-EPMC9743422 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Identification of a Target Site for Covalent Inhibition of Protein Phosphohistidine Phosphatase 1.

Kim Hyeong Jun HJ Jung Hoyoung H Kim Soyeon S Seo Jeong Kon JK Kee Jung-Min JM

ACS medicinal chemistry letters 20221128 12

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 therapeuti ...[more]

PMID: 36518699

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