Sim Edith, Westwood Isaac, Fullam Elizabeth
University of Oxford, Department of Pharmacology, Mansfield Road, Oxford, UK.
Expert Opin Drug Metab Toxicol. 2007 Apr;3(2):169-84. doi: 10.1517/17425255.3.2.169.
Arylamine N-acetyltransferases (NATs), known as drug- and carcinogen-metabolising enzymes, have had historic roles in cellular metabolism, carcinogenesis and pharmacogenetics, including epidemiological studies of disease susceptibility. NAT research in the past 5 years builds on that history and additionally paves the way for establishing the following new concepts in biology and opportunities in drug discovery: i) NAT polymorphisms can be used as tools in molecular anthropology to study human evolution; ii) tracing NAT protein synthesis and degradation within cells is providing insight into protein folding in cell biology; iii) studies on control of NAT gene expression may help to understand the increase in the human NAT isoenzyme, NAT1, in breast cancer; iv) a NAT homologue in mycobacteria plays an essential role in cell-wall synthesis and mycobacterial survival inside host macrophage, thus identifying a novel biochemical pathway; v) transgenic mice, with genetic modifications of all Nat genes, provide in vivo tools for drug metabolism; and vi) structures of NAT isoenzymes provide essential in silico tools for drug discovery.
芳胺N-乙酰基转移酶（NATs），作为药物和致癌物代谢酶，在细胞代谢、致癌作用和药物遗传学中发挥了重要历史作用，包括疾病易感性的流行病学研究。过去5年的NAT研究在这一历史基础上进一步发展，为生物学中的以下新概念的确立和药物发现的机会铺平了道路：i）NAT多态性可作为分子人类学工具用于研究人类进化；ii）追踪细胞内NAT蛋白质的合成和降解为细胞生物学中的蛋白质折叠提供了深入了解；iii）对NAT基因表达调控的研究可能有助于理解乳腺癌中人类NAT同工酶NAT1的增加；iv）分枝杆菌中的一种NAT同源物在细胞壁合成和宿主巨噬细胞内分枝杆菌的存活中起重要作用，从而确定了一条新的生化途径；v）对所有Nat基因进行基因改造的转基因小鼠为药物代谢提供了体内工具；vi）NAT同工酶的结构为药物发现提供了重要的计算机辅助工具。
