期刊
BIOTECHNOLOGY AND BIOENGINEERING
卷 93, 期 3, 页码 494-499出版社
WILEY
DOI: 10.1002/bit.20744
关键词
cytochrome P450BM3; drug metabolites; drug metabolism; bioconversion; peroxide shunt; directed evolution
资金
- NIGMS NIH HHS [R01 GM068664-01] Funding Source: Medline
Testing the toxicities and biological activities of the human metabolites of drugs is important for development of safe and effective pharmaceuticals. Producing these metabolites using human cytochrome P450s is difficult, however, because the human enzymes are costly, poorly stable, and slow. We have used directed evolution to generate variants of P450 BM3 from Bacillus megaterium that function via the peroxide shunt pathway, using hydrogen peroxide in place of the reductase domain, oxygen and NADPH. Here, we report further evolution of the P450 BM3 heme domain peroxygenase to enhance production of the authentic human metabolites of propranolol by this biocatalytic route. This system offers a versatile, cost-effective, and scaleable route to the synthesis of drug metabolites. (c) 2005 Wiley Periodicals, Inc.
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