Zhang Naixia, Liu Li, Liu Fen, Wagner Carston R, Hanna Patrick E, Walters Kylie J
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
J Mol Biol. 2006 Oct 13;363(1):188-200. doi: 10.1016/j.jmb.2006.08.026. Epub 2006 Aug 15.
Arylamine N-acetyltransferases (NATs) catalyze the acetylation of arylamines, a key step in the detoxification of many carcinogens. The determinants of NAT substrate specificity are not known, yet this knowledge is required to understand why NAT enzymes acetylate some arylamines, but not others. Here, we use NMR spectroscopy and homology modeling to reveal the structural determinants of arylamine acetylation by NATs. In particular, by using chemical shift perturbation analysis, we have identified residues that play a critical role in substrate binding and catalysis. This study reveals why human NAT1 acetylates the sunscreen additive p-aminobenzoic acid and tobacco smoke carcinogen 4-aminobiphenyl, but not o-toluidine and other arylamines linked to bladder cancer. Our results represent an important step toward predicting whether arylamines present in new products can be detoxified by mammalian NATs.
芳胺N - 乙酰基转移酶（NATs）催化芳胺的乙酰化反应，这是许多致癌物解毒过程中的关键步骤。NAT底物特异性的决定因素尚不清楚，但要理解为什么NAT酶能使某些芳胺乙酰化而不能使其他芳胺乙酰化，就需要这方面的知识。在这里，我们使用核磁共振光谱和同源建模来揭示NATs对芳胺进行乙酰化反应的结构决定因素。特别是，通过化学位移扰动分析，我们确定了在底物结合和催化中起关键作用的残基。这项研究揭示了为什么人类NAT1能使防晒添加剂对氨基苯甲酸和烟草烟雾致癌物4 - 氨基联苯乙酰化，却不能使邻甲苯胺和其他与膀胱癌相关的芳胺乙酰化。我们的研究结果朝着预测新产品中存在的芳胺是否能被哺乳动物NATs解毒迈出了重要一步。
