期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 15, 期 43, 页码 11723-11729出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.200900643
关键词
C-H activation; cytochrome P450; drug development; drug metabolism; oxidation
资金
- NIH [GM068664]
- Jacobs Institute
- Eli Lilly and Co
- NSF
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM068664] Funding Source: NIH RePORTER
Herein we demonstrate that a small panel of variants of cytochrome P450 BM3 from Bacillus megaterium covers the breadth of reactivity of human P450s by producing 12 of 13 mammalian metabolites for two marketed drugs, verapamil and astemizole, and one research compound. The most active enzymes support preparation of individual metabolites for preclinical bioactivity and toxicology evaluations. Underscoring their potential utility in drug lead diversification, engineered P450 BM3 variants also produce novel metabolites by catalyzing reactions at carbon centers beyond those targeted by animal and human P450s. Production of a specific metabolite can be improved by directed evolution of the enzyme catalyst. Some variants are more active on the more hydrophobic parent drug than on its metabolites, which limits production of multiply-hydroxylated species, a preference that appears to depend on the evolutionary history of the P450 variant.
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