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首页> 外文期刊>Chemistry: A European journal >Dissecting the Cytochrome P450 1A2- and 3A4-Mediated Metabolism of Aflatoxin B1 in Ligand and Protein Contributions
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Dissecting the Cytochrome P450 1A2- and 3A4-Mediated Metabolism of Aflatoxin B1 in Ligand and Protein Contributions

机译：解剖细胞色素P450 1A2-和3A4介导的配体和蛋白质贡献中的黄曲霉毒素B1的代谢

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摘要

Aflatoxin B1 (AFB1) is a chemically intriguing compound because it has several potential sites of metabolism (SOMs), although only some of them are observed experimentally. Cytochrome P450 (CYP) 3A4 and 1A2 are the major isoforms involved in its metabolism. Here, we systematically investigate reactivity and accessibility of all possible SOMs in these two CYPs to elucidate AFB1 metabolism. DFT calculations were used to determine activation energies for each possible reaction. Aliphatic hydroxylation on position 9A and 3a are energetically favored, whereas position 9 is the preferred site for epoxidation. Docking studies, molecular dynamics (MD) simulations, and free energy (MM/GBSA) calculations were applied to elucidate the accessibility of each SOM. The most stable binding modes in CYP3A4 favor the formation of the 3a-hydroxylated and 8,9-exo-epoxide metabolites. Conversion of the methoxy group is also sterically possible, but not observed experimentally due to its low reactivity. In the CYP1A2 active site, AFB1 cannot orient position 3 towards the catalytic center, whereas the 8,9-exo-epoxide and 9A-hydroxylated metabolites are formed from the most stable and the 8,9-endo-epoxide from a less stable binding mode, respectively. The results agree with experimental data and suggest that both reactivity and the shape of the enzyme active site need to be considered to understand the distribution of SOMs and to improve current SOM prediction methods.
机译：黄曲霉毒素B1（AFB1）是一种化学迷恋化合物，因为它具有几个潜在的代谢位点（SOM），尽管仅通过实验观察它们中的一些潜在的代谢位点。细胞色素P450（CYP）3A4和1A2是涉及其新陈代谢的主要同种型。在这里，我们系统地研究了这两种CYP中所有可能SOM的反应性和可访问性，以阐明AFB1代谢。 DFT计算用于确定每个可能的反应的激活能量。在位置9a和3a上的脂族羟基化是有利的青睐，而位置9是用于环氧化的优选部位。对接研究，分子动力学（MD）模拟和自由能量（MM / GBSA）计算用于阐明每个SOM的可访问性。 CYP3A4中最稳定的结合模式有利于形成3A-羟基化和8,9- exo-环氧化代谢物。甲氧基的转化率也是可能的，但由于其低反应性，未经实验观察。在CYP1A2活性位点中，AFB1不能向催化中心定向位置3，而8,9- exo-环氧化和9A-羟基化代谢物由最稳定的稳定性结合的最稳定和8,9-末端 - 环氧化物形成模式分别。结果与实验数据一致，并表明酶活性和酶活性位点的形状需要考虑了解SOM的分布并改善电流SOM预测方法。

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