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Preparation of human metabolites of propranolol using laboratory‐evolved bacterial cytochromes P450

Otey, Christopher R. and Bandara, Geethani and Lalonde, James and Takahashi, Katsuyuki and Arnold, Frances H. (2006) Preparation of human metabolites of propranolol using laboratory‐evolved bacterial cytochromes P450. Biotechnology and Bioengineering, 93 (3). pp. 494-499. ISSN 0006-3592. http://resolver.caltech.edu/CaltechAUTHORS:20180821-155634350

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1002/bit.20744DOIArticle
ORCID:
AuthorORCID
Arnold, Frances H.0000-0002-4027-364X
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.
Funders:
Funding AgencyGrant Number
NIHR01 GM068664-0
Subject Keywords:cytochrome P450 BM3; drug metabolites; drug metabolism; bioconversion; peroxide shunt; directed evolution
Record Number:CaltechAUTHORS:20180821-155634350
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20180821-155634350
Official Citation:Otey, C. R., Bandara, G. , Lalonde, J. , Takahashi, K. and Arnold, F. H. (2006), Preparation of human metabolites of propranolol using laboratory‐evolved bacterial cytochromes P450. Biotechnol. Bioeng., 93: 494-499. doi:10.1002/bit.20744
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:88998
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Aug 2018 23:03
Last Modified:21 Aug 2018 23:03

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