Grant D M
Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S1A8, Canada.
Curr Drug Metab. 2008 Jul;9(6):465-70. doi: 10.2174/138920008784892029.
A large body of biochemical, kinetic and molecular information, accumulated over the course of more than 80 years, has produced valuable insights into the relationship between the structures and the catalytic functions of the human arylamine N-acetyltransferases NAT1 and NAT2. Much of the groundwork for the determination of human NAT structures and functions was provided by seminal biochemical and enzyme kinetic studies in both human and non-human model systems, the cloning and primary amino acid sequence determination of eukaryotic and prokaryotic NATs, the characterization of naturally occurring and artificially mutated forms of human NATs, elucidation of the crystal structures of several prokaryotic NAT orthologues, and information that has been derived from cross-species comparisons. In 2007 the progress of these studies was aided substantially by the successful crystallization and direct structural analysis of human NAT1 and NAT2. The purpose of this review is to give a brief historical perspective, to summarize our current understanding of human NAT structures and functions based on both earlier and more recent work, and to provide some future insights into the potential applications of this information to the prediction of therapeutic and toxic outcomes associated with the acetylation of primary aromatic amine- and hydrazine-containing chemicals.
八十多年来积累的大量生化、动力学和分子信息，使人们对人类芳胺N - 乙酰基转移酶NAT1和NAT2的结构与催化功能之间的关系有了宝贵的认识。人类NAT结构和功能测定的许多基础工作是由人类和非人类模型系统中的开创性生化和酶动力学研究、真核和原核NAT的克隆及一级氨基酸序列测定、人类NAT天然存在和人工突变形式的表征、几种原核NAT同源物晶体结构的阐明以及跨物种比较得出的信息所提供的。2007年，人类NAT1和NAT2的成功结晶及直接结构分析极大地推动了这些研究的进展。本综述的目的是给出一个简要的历史视角，基于早期和近期的工作总结我们目前对人类NAT结构和功能的理解，并对这些信息在预测与含伯芳香胺和肼的化学物质乙酰化相关的治疗和毒性结果方面的潜在应用提供一些未来的见解。
