Substrate selectivity of mouse N-acetyltransferases 1, 2, and 3 expressed in COS-1 cells.
Substrate selectivity of mouse N-acetyltransferases 1, 2, and 3 expressed in COS-1 cells.
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发表时间：
1998-05
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通讯作者：
L. Estrada-Rodgers;G. Levy;W. Weber
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作者：
L. Estrada-Rodgers;G. Levy;W. Weber
已鉴定出两种人乙酰辅酶A：芳香胺N-乙酰基转移酶(NAT1和NAT2)。作为这些同工酶底物的治疗和致癌药物(包括异烟肼、磺胺二甲嘧啶、对氨基苯甲酸、5-氨基水杨酸和2-氨基荧烯)已被用于评估NAT1和NAT2的N-乙酰化多态在治疗疾病和不同乙酰化表型个体之间不同癌症风险中的作用。小鼠经常被用作人类乙酰化基因多态的模型。由于已经在小鼠体内鉴定出三种NAT同工酶，因此有必要测定小鼠NAT对常见NAT底物的选择性。在本研究中，在COS-1细胞中表达了Nat1*、Nat2*8和Nat3*，并用不同的底物评价了它们的底物选择性。在所用条件下，小鼠Nat2对对氨基苯甲酸、5-氨基水杨酸和2-氨基荧烯的催化活性分别是Nat1的20倍、2.4倍和5.4倍。异烟肼的N-乙酰化反应仅由小鼠的Nat1催化。对于本研究中测试的底物，小鼠Nat3只对5-氨基水杨酸表现出活性，并且只有Nat2显示的1/20的活性。此外，第一个被鉴定的内源性NAT底物对氨基苯甲酰谷氨酸对小鼠NAT 2具有选择性。这些结果进一步支持了小鼠Nat2和人Nat1的功能相似。
Two human acetyl-CoA:arylamine N-acetyltransferases (NAT1 and NAT2) have been identified. Therapeutic and carcinogenic agents that are substrates for these isoenzymes (including isoniazid, sulfamethazine, p-aminobenzoic acid, 5-aminosalicyclic acid, and 2-aminofluorene) have been used to evaluate the role of the N-acetylation polymorphisms of NAT1 and NAT2 in the treatment of disease and differential risk of various cancers among individuals of differing acetylator phenotypes. The mouse is frequently used as a model of the human acetylator polymorphism. As three Nat isoenzymes have been identified in mouse, it is necessary to determine the selectivity of mouse Nats toward common NAT substrates. In the present study, Nat1*, Nat2*8, and Nat3* were expressed in COS-1 cells, and their substrate selectivity was evaluated with various substrates. Under the conditions used, mouse Nat2 had 20-, 2.4-, and 5.4-fold higher catalytic activity for p-aminobenzoic acid, 5-aminosalicylic acid, and 2-aminofluorene, respectively, than Nat1. Isoniazid N-acetylation was catalyzed only by mouse Nat1. For the substrates tested in this study, mouse Nat3 exhibited activity only toward 5-aminosalicylic acid and only at 1/20 the activity shown by Nat2. In addition, p-aminobenzoylglutamate, the first endogenous NAT substrate identified, was selective for mouse Nat2. These results further support the functional analogy of mouse Nat2 and human NAT1.