Genome Integrity and Structural Biology Laboratory (L.C.P., L.G.P., A.M.K.) and Reproductive and Developmental Biology Laboratory (M.Y.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; and Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (L.G.P.)
Genome Integrity and Structural Biology Laboratory (L.C.P., L.G.P., A.M.K.) and Reproductive and Developmental Biology Laboratory (M.Y.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; and Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (L.G.P.).
Drug Metab Dispos. 2022 Jul;50(7):1027-1041. doi: 10.1124/dmd.121.000478. Epub 2022 Feb 22.
Sulfotransferases are ubiquitous enzymes that transfer a sulfo group from the universal cofactor donor 3'-phosphoadenosine 5'-phosphosulfate to a broad range of acceptor substrates. In humans, the cytosolic sulfotransferases are involved in the sulfation of endogenous compounds such as steroids, neurotransmitters, hormones, and bile acids as well as xenobiotics including drugs, toxins, and environmental chemicals. The Golgi associated membrane-bound sulfotransferases are involved in post-translational modification of macromolecules from glycosaminoglycans to proteins. The sulfation of small molecules can have profound biologic effects on the functionality of the acceptor, including activation, deactivation, or enhanced metabolism and elimination. Sulfation of macromolecules has been shown to regulate a number of physiologic and pathophysiological pathways by enhancing binding affinity to regulatory proteins or binding partners. Over the last 25 years, crystal structures of these enzymes have provided a wealth of information on the mechanisms of this process and the specificity of these enzymes. This review will focus on the general commonalities of the sulfotransferases, from enzyme structure to catalytic mechanism as well as providing examples into how structural information is being used to either design drugs that inhibit sulfotransferases or to modify the enzymes to improve drug synthesis. SIGNIFICANCE STATEMENT: This manuscript honors Dr. Masahiko Negishi's contribution to the understanding of sulfotransferase mechanism, specificity, and roles in biology by analyzing the crystal structures that have been solved over the last 25 years.
磺基转移酶是普遍存在的酶，它将 3'-磷酸腺苷 5'-磷酸硫酸中的磺酰基转移到广泛的受体底物上。在人类中，细胞质磺基转移酶参与内源性化合物如类固醇、神经递质、激素和胆汁酸以及包括药物、毒素和环境化学物质在内的外源化合物的磺化作用。高尔基相关的膜结合磺基转移酶参与糖胺聚糖到蛋白质等大分子的翻译后修饰。小分子的磺化作用可以对受体的功能产生深远的生物学影响，包括激活、失活或增强代谢和消除。磺化大分子已被证明通过增强与调节蛋白或结合伴侣的结合亲和力来调节许多生理和病理生理途径。在过去的 25 年中，这些酶的晶体结构提供了大量关于该过程的机制和这些酶的特异性的信息。这篇综述将重点介绍磺基转移酶的一般共性，从酶结构到催化机制，并提供一些例子来说明如何利用结构信息来设计抑制磺基转移酶的药物或修饰酶以提高药物合成。意义陈述：本文通过分析过去 25 年中已解决的晶体结构，向 Masahiko Negishi 博士对磺基转移酶机制、特异性和在生物学中的作用的理解表示敬意。
