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Published November 2, 2009 | Supplemental Material
Journal Article Open

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

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.

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.

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