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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. doi:10.1002/chem.200900643. https://resolver.caltech.edu/CaltechAUTHORS:20180823-144311628

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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
https://doi.org/10.1002/chem.200900643DOIArticle
ORCID:
AuthorORCID
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2009 WILEY‐VCH. Received: March 10, 2009. Revised: August 11, 2009. Published online: September 22, 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 for MedicineUNSPECIFIED
Eli LillyUNSPECIFIED
NSF Predoctoral FellowshipUNSPECIFIED
Subject Keywords:C-H activation · cytochrome P450 · drug development · drug metabolism · oxidation
Issue or Number:43
DOI:10.1002/chem.200900643
Record Number:CaltechAUTHORS:20180823-144311628
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20180823-144311628
Official Citation:Sawayama, A. , Chen, M. , Kulanthaivel, P. , Kuo, M. , Hemmerle, H. and Arnold, F. (2009), A Panel of Cytochrome P450 BM3 Variants to Produce Drug Metabolites and Diversify Lead Compounds. Chem. Eur. J., 15: 11723-11729. doi:10.1002/chem.200900643
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:89111
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:23 Aug 2018 22:41
Last Modified:16 Nov 2021 00:32

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