Preparation of human metabolites of propranolol using laboratory‐evolved bacterial cytochromes P450
Abstract
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.
Additional Information
© 2005 Wiley Periodicals, Inc. Received 27 June 2005; accepted 31 August 2005. The authors thank Professor Wendel Nelson for generously providing the 4' and 5'-hydroxypropranolol standards and James Ross for laboratory assistance. Geethani Bandara and Christopher R. Otey contributed equally to this study. Contract grant sponsor: National Institutes of Health. Contract grant number: R01 GM068664-0.Additional details
- Eprint ID
- 88998
- DOI
- 10.1002/bit.20744
- Resolver ID
- CaltechAUTHORS:20180821-155634350
- R01 GM068664-0
- NIH
- Created
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2018-08-21Created from EPrint's datestamp field
- Updated
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2021-11-16Created from EPrint's last_modified field