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

Hyeong Jun Kim; Hoyoung Jung; Soyeon Kim; Jeong Kon Seo; Jung-Min Kee

doi:10.1021/acsmedchemlett.2c00450

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

ACS Med Chem Lett. 2022 Nov 28;13(12):1911-1915. doi: 10.1021/acsmedchemlett.2c00450. eCollection 2022 Dec 8.

Authors

Hyeong Jun Kim¹, Hoyoung Jung¹, Soyeon Kim¹, Jeong Kon Seo^{2

3}, Jung-Min Kee¹

Affiliations

¹ Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea.
² UNIST Central Research Facilities (UCRF), Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea.
³ Graduate School of Semiconductor Materials and Devices Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea.

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.