Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS EAC4413, 75013, Paris, France.
Expert Opin Drug Metab Toxicol. 2013 Mar;9(3):349-62. doi: 10.1517/17425255.2013.742505. Epub 2013 Jan 7.
Arylamine N-acetyltransferases (NATs) are polymorphic xenobiotic metabolizing enzymes catalyzing the acetylation of aromatic amine chemicals of pharmacological/toxicological relevance (drugs, carcinogens). NATs are primordial determinants of the detoxification and/or bioactivation of these compounds. These enzymes are found in prokaryotes and eukaryotes. Several NAT isoenzymes may be present in one organism, and their substrate specificity profile and pattern of tissue expression suggest distinct functional roles.
Many advances in NAT mechanism, substrate specificity, and functional impact of polymorphism have come from crystallographic and NMR studies. To date, the crystal structures of 10 different NAT homologues have been solved, including two human isoforms and several bacterial NATs. The authors present the most recent snapshot in NAT structure differences and similarities. The authors also depict the structural bases of substrate/inhibitor recognition and specificity, cofactor binding, catalytic mechanism, genetic regulation (polymorphism), and enzyme inhibition.
The determination of other NATs structures will help to develop specific inhibitors of NAT enzymes with potential clinical relevance. In addition, it will contribute to the identification of endogenous substrates and novel functions associated to this family of enzymes.
芳香胺 N-乙酰基转移酶（NATs）是多态性的外源性代谢酶，可催化具有药理/毒理学相关性的芳香胺类化学物质（药物、致癌物）的乙酰化。NATs 是这些化合物解毒和/或生物活化的原始决定因素。这些酶存在于原核生物和真核生物中。一种生物体中可能存在几种 NAT 同工酶，其底物特异性谱和组织表达模式表明其具有不同的功能作用。
NAT 机制、底物特异性和多态性的功能影响方面的许多进展来自于晶体学和 NMR 研究。迄今为止，已经解决了 10 种不同 NAT 同源物的晶体结构，包括两种人类同工酶和几种细菌 NAT。作者呈现了 NAT 结构差异和相似性的最新快照。作者还描绘了底物/抑制剂识别和特异性、辅因子结合、催化机制、遗传调控（多态性）和酶抑制的结构基础。
确定其他 NAT 的结构将有助于开发具有潜在临床相关性的 NAT 酶的特异性抑制剂。此外，它将有助于鉴定与该酶家族相关的内源性底物和新功能。
