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A Panel of Cytochrome P450 BM3 Variants to Produce Drug Metabolites and Diversify Lead Compounds

Sawayama, Andrew M. and Chen, Michael M. Y. and Kulanthaivel, Palaniappan and Kuo, Ming-Shang and Hemmerle, Horst and Arnold, Frances H. (2009) A Panel of Cytochrome P450 BM3 Variants to Produce Drug Metabolites and Diversify Lead Compounds. Chemistry: a European Journal, 15 (43). pp. 11723-11729. ISSN 0947-6539. PMCID PMC3118466. doi:10.1002/chem.200900643. https://resolver.caltech.edu/CaltechAUTHORS:20091210-103923398

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1002/chem.200900643DOIArticle
http://www3.interscience.wiley.com/journal/122603781/abstract?CRETRY=1&SRETRY=0PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118466PubMed CentralArticle
ORCID:
AuthorORCID
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2009 Wiley. Received: 10 March 2009; revised: 11 August 2009. Published Online: 22 Sep 2009. This work was supported in part by NIH grant GM068664, the Jacobs Institute for Molecular Engineering and Medicine at Caltech, Eli Lilly and Co., and an NSF predoctoral fellowship to MMYC. We thank Dr. Terry Lindstrom for a critical reading of the manuscript.
Funders:
Funding AgencyGrant Number
NIHGM068664
Jacobs Institute for Molecular Engineering and MedicineUNSPECIFIED
Eli Lilly and Co.UNSPECIFIED
NSFUNSPECIFIED
Subject Keywords:C-H activation; cytochrome P450; drug development; drug metabolism; oxidation
Issue or Number:43
PubMed Central ID:PMC3118466
DOI:10.1002/chem.200900643
Record Number:CaltechAUTHORS:20091210-103923398
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20091210-103923398
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:16940
Collection:CaltechAUTHORS
Deposited By:INVALID USER
Deposited On:10 Dec 2009 21:27
Last Modified:08 Nov 2021 23:31

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