Key mutations alter the cytochrome P450 BM3 conformational landscape and remove inherent substrate bias

Abstract

Background: P450 BM3 is a high activity enzyme with biotechnological potential. Results: Mutations perturbing P450 BM3's conformational state and active site facilitate human P450-like oxidation of the drug omeprazole. Conclusion: Conformational destabilization enables P450 BM3 to explore novel conformations and accept diverse substrates. Significance: " Gatekeeper" mutations that decrease the energetic barrier for transition to the substrate-bound state can reconfigure P450 BM3 specificity and reactivity. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.