Journal
DRUG METABOLISM AND DISPOSITION
Volume 36, Issue 11, Pages 2166-2170Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/dmd.108.021220
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Funding
- 21C Frontier Microbial Genomics and Application Center Program of the Ministry of Education, Science and Technology of the Republic of Korea
- Biocatalyst Technology Innovation [C-Yongu-2005-05-KRIBB]
- Korea Research Council of Fundamental Science and Technology
- Korean Government (MOEHRD) [KRF-2006-005-J03003]
- Ministry of Education, Science and Technology of the Republic of Korea
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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.
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