Kim Dong-Hyun, Kim Keon-Hee, Kim Dae-Hwan, Liu Kwang-Hyeon, Jung Heung-Chae, Pan Jae-Gu, Yun Chul-Ho
School of Biological Sciences and Technology and Hormone Research Center, Chonnam National University, Gwangju 500-757, Republic of Korea.
Drug Metab Dispos. 2008 Nov;36(11):2166-70. doi: 10.1124/dmd.108.021220. Epub 2008 Jul 31.
Recently, wild-type and mutant forms of bacterial cytochrome P450 BM3 (CYP102A1) have been found to metabolize various drugs through reactions similar to those catalyzed by human cytochromes P450 (P450s). Therefore, it has been suggested that CYP102A1 may be used to produce large quantities of the metabolites of human P450-catalyzed reactions. In this report, we show that the oxidation of 7-ethoxycoumarin, a typical human P450 substrate, is catalyzed by both wild-type and mutant forms of CYP102A1. Two major products were produced as a result of O-deethylation and 3-hydroxylation reactions. These results demonstrate that CYP102A1 mutants catalyze the same reactions as human P450s. High noncompetitive intermolecular kinetic deuterium isotope effects were observed for 7-ethoxycoumarin O-deethylation in the CYP102A1 system. These results suggest that there is a common mechanism for the oxidation reactions catalyzed by both the bacterial CYP102A1 and human P450 enzymes.
最近，已发现细菌细胞色素P450 BM3（CYP102A1）的野生型和突变型可通过与人类细胞色素P450（P450s）催化的反应类似的反应来代谢各种药物。因此，有人提出CYP102A1可用于大量生产人类P450催化反应的代谢产物。在本报告中，我们表明，典型的人类P450底物7-乙氧基香豆素的氧化反应可由CYP102A1的野生型和突变型催化。O-脱乙基化和3-羟基化反应产生了两种主要产物。这些结果表明，CYP102A1突变体催化的反应与人类P450s相同。在CYP102A1系统中，观察到7-乙氧基香豆素O-脱乙基化具有较高的非竞争性分子间动力学氘同位素效应。这些结果表明，细菌CYP102A1和人类P450酶催化的氧化反应存在共同机制。
