Dillenburg Maxwell, Smith Jacob, Wagner Carston R
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
ACS Pharmacol Transl Sci. 2023 Jul 20;6(10):1310-1322. doi: 10.1021/acsptsci.3c00079. eCollection 2023 Oct 13.
The histidine triad nucleotide binding protein 1 (HINT1) is a nucleoside phosphoramidase that has garnered interest due to its widespread expression and participation in a broad range of biological processes. Herein, we discuss the role of HINT1 as a regulator of several CNS functions, tumor suppressor, and mast cell activator via its interactions with multiple G-protein-coupled receptors and transcription factors. Importantly, altered HINT1 expression and mutation are connected to the progression of multiple disease states, including several neuropsychiatric disorders, peripheral neuropathy, and tumorigenesis. Additionally, due to its involvement in the activation of several clinically used phosphoramidate prodrugs, tremendous efforts have been made to better understand the interactions behind nucleoside binding and phosphoramidate hydrolysis by HINT1. We detail the substrate specificity and catalytic mechanism of HINT1 hydrolysis, while highlighting the structural biology behind these efforts. The aim of this review is to summarize the multitude of biological and pharmacological functions in which HINT1 participates while addressing the areas of need for future research.
组氨酸三联体核苷酸结合蛋白1（HINT1）是一种核苷磷酸酰胺酶，因其广泛表达并参与多种生物学过程而受到关注。在此，我们讨论HINT1通过与多种G蛋白偶联受体和转录因子相互作用，作为几种中枢神经系统功能的调节因子、肿瘤抑制因子和肥大细胞激活剂的作用。重要的是，HINT1表达改变和突变与多种疾病状态的进展有关，包括几种神经精神疾病、周围神经病变和肿瘤发生。此外，由于其参与了几种临床使用的磷酰胺酯前药的激活，人们已做出巨大努力以更好地理解HINT1核苷结合和磷酰胺酯水解背后的相互作用。我们详细阐述了HINT1水解的底物特异性和催化机制，同时强调这些研究背后的结构生物学。本综述的目的是总结HINT1参与的众多生物学和药理学功能，同时探讨未来研究的需求领域。
