PharmGKB summary: very important pharmacogene information for N-acetyltransferase 2.
PharmGKB summary: very important pharmacogene information for N-acetyltransferase 2.
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DOI：
10.1097/fpc.0000000000000062
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发表时间：
2014-08
影响因子：
2.6
通讯作者：
Klein TE
中科院分区：
文献类型：
--
作者：
McDonagh EM;Boukouvala S;Aklillu E;Hein DW;Altman RB;Klein TE
背景芳胺N-乙酰转移酶(NAT)是一种外源代谢酶，目前已有三种不同的酶活性被描述[1]。第一个(EC 2.3.1.5)涉及依赖于乙酰辅酶A(CoA)的芳胺和芳基肼的N-乙酰化，这一反应通常与异物解毒有关。第二个(EC 2.3.1.118)也是乙酰辅酶A依赖的，涉及N-羟基芳胺的O-乙酰化[2]，通常通过细胞色素P450酶对芳胺的N-氧化产生。第三个(EC 2.3.1.56)是在N-芳基异羟肟酸上进行的不依赖于乙酰辅酶A的N，O-乙酰基转移，产生与DNA结合的高活性诱变化合物。NAT在外源物质和治疗药物的代谢和解毒过程中起着重要的作用，并且由于它们在致癌物的激活或解毒以及它们与环境化学物质的相互作用中的作用而与癌症风险有关[3-5]。人类中存在两个不同的NAT基因(NAT 1和NAT 2)，它们在基因结构、遗传变异程度、发育模式和组织表达方面存在差异[6-8]。它们的蛋白质产物具有不同的生理作用，尽管结构相似，但关键残基的不同导致不同的底物分布/亲和力[6，7，9]。Nat1普遍表达，因此可能参与动态平衡和发育，尽管表达水平在细胞类型和组织中有所不同[3，8，10-12]。Nat2主要在肝脏、小肠和结肠组织中表达，因此被认为是一种典型的异物代谢酶[3，8，10，12，13]，尽管在大多数组织中都可以发现基本的Nat2mRNA水平[2]。
BackgroundFunction and expression Arylamine N-acetyltransferases (NATs) are xenobioticmetabolizing enzymes for which three distinct enzymatic activities have been described [1]. The first (EC 2.3. 1.5) involves acetyl coenzyme A (CoA)-dependent N-acetylation of arylamines and arylhydrazines, a reaction usually associated with xenobiotic detoxification. The second (EC 2.3. 1.118) is also acetyl-CoA dependent and involves O-acetylation of N-hydroxyarylamines [2], typically generated through N-oxidation of arylamines by cytochrome P450 enzymes. The third (EC 2.3. 1.56) is an acetyl-CoA-independent N, O-acetyltransfer performed on N-arylhydroxamic acids, generating highly reactive mutagenic compounds that bind to DNA. NATs play important roles in the metabolism and detoxification of xenobiotics and therapeutic drugs and are implicated in cancer risk because of their role in the activation or detoxification of carcinogens and their interaction with environmental chemicals [3–5].Two NAT genes (NAT1 and NAT2) have been characterized in humans, which differ in gene structure, extent of genetic variation, pattern of developmental and tissue expression [6–8]. Their protein products have different physiological roles, and despite being structurally similar, differences in key residues result in different substrate profiles/affinities [6, 7, 9]. NAT1 is ubiquitously expressed and therefore may be involved in homeostasis and development, although the levels of expression vary between cell types and tissues [3, 8, 10–12]. NAT2 expression is found predominantly in the liver, small intestine and colon tissues, and thus is regarded a typical xenobiotic-metabolizing enzyme [3, 8, 10, 12, 13], although basal NAT2 mRNA levels can be found in most tissues [2].