Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery.
Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery.
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芳基胺N-乙酰转移酶：从药物代谢和药物遗传学到药物发现。
DOI：
10.1111/bph.12598
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发表时间：
2014-06
影响因子：
7.3
通讯作者：
Ryan A
中科院分区：
文献类型：
--
作者：
Sim E;Abuhammad A;Ryan A
芳胺 N-乙酰转移酶 (NAT) 是多态性药物代谢酶，可乙酰化芳胺致癌物和药物，包括肼屈嗪和磺胺类药物。缓慢的 NAT 表型增加了对肼屈嗪和异烟肼毒性以及职业性膀胱癌的易感性。两个多态性人类 NAT 位点显示连锁不平衡。所有哺乳动物 Nat 基因均具有无内含子开放阅读框和非编码外显子。人类基因产物 NAT1 和 NAT2 具有不同的底物特异性：NAT2 乙酰化肼屈嗪，而人 NAT1 乙酰化对氨基水杨酸 (p-AS) 和叶酸分解代谢物对氨基苯甲酰谷氨酸 (p-abaglu)。人类NAT2主要存在于肝脏和肠道中。人类 NAT1 及其小鼠同源物存在于许多成体组织和早期胚胎中。人类 NAT1 在雌激素受体阳性乳腺癌中强烈表达，可能有助于叶酸和乙酰 CoA 体内平衡。 NAT 酶通过 Cys、His 和 Asp 催化三联体发挥作用，具有活性位点调节特异性的结构。多态性可能导致蛋白质折叠。 C 末端有助于结合乙酰 CoA，并且在 NAT（包括原核同源物）之间存在差异。鼠伤寒沙门氏菌中的 NAT 支持致癌物激活，分枝杆菌中的 NAT 代谢异烟肼，而多态性是异烟肼耐药性的次要因素。重要的是，nat 属于结核分枝杆菌在巨噬细胞内生存所必需的基因簇。 NAT 抑制剂是新型抗结核药物的起点。人类 NAT1 特异性抑制剂可能在乳腺癌生物标志物检测和癌症治疗中发挥作用。 NAT 抑制剂与 5-氨基水杨酸盐 (5-AS) 联合用药治疗炎症性肠病，促使人们不断研究肠道细菌中的偶氮还原酶，这些酶从包括巴柳氮在内的前药中释放 5-AS。
Arylamine N-acetyltransferases (NATs) are polymorphic drug-metabolizing enzymes, acetylating arylamine carcinogens and drugs including hydralazine and sulphonamides. The slow NAT phenotype increases susceptibility to hydralazine and isoniazid toxicity and to occupational bladder cancer. The two polymorphic human NAT loci show linkage disequilibrium. All mammalian Nat genes have an intronless open reading frame and non-coding exons. The human gene products NAT1 and NAT2 have distinct substrate specificities: NAT2 acetylates hydralazine and human NAT1 acetylates p-aminosalicylate (p-AS) and the folate catabolite para-aminobenzoylglutamate (p-abaglu). Human NAT2 is mainly in liver and gut. Human NAT1 and its murine homologue are in many adult tissues and in early embryos. Human NAT1 is strongly expressed in oestrogen receptor-positive breast cancer and may contribute to folate and acetyl CoA homeostasis. NAT enzymes act through a catalytic triad of Cys, His and Asp with the architecture of the active site-modulating specificity. Polymorphisms may cause unfolded protein. The C-terminus helps bind acetyl CoA and differs among NATs including prokaryotic homologues. NAT in Salmonella typhimurium supports carcinogen activation and NAT in mycobacteria metabolizes isoniazid with polymorphism a minor factor in isoniazid resistance. Importantly, nat is in a gene cluster essential for Mycobacterium tuberculosis survival inside macrophages. NAT inhibitors are a starting point for novel anti-tuberculosis drugs. Human NAT1-specific inhibitors may act in biomarker detection in breast cancer and in cancer therapy. NAT inhibitors for co-administration with 5-aminosalicylate (5-AS) in inflammatory bowel disease has prompted ongoing investigations of azoreductases in gut bacteria which release 5-AS from prodrugs including balsalazide.
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影响因子：
4.8
作者：
Butcher, NJ;Arulpragasam, A;Minchin, RF
通讯作者：
Minchin, RF
影响因子：
4.1
作者：
Boukouvala, S;Price, N;Sim, E
通讯作者：
Sim, E
DOI：
10.1111/j.1742-7843.2005.pto_02.x
发表时间：
2005-05-01
影响因子：
3.1
作者：
Boukouvala, S;Sim, E
通讯作者：
Sim, E
DOI：
10.1097/00008571-200207000-00006
发表时间：
2002-07-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
Boukouvala, S;Price, N;Sim, E
通讯作者：
Sim, E
影响因子：
2.8
作者：
Cao, W;Chau, B;Erickson, RP
通讯作者：
Erickson, RP