The Evolution of Cytochrome P450 Enzymes as Biocatalysts in Drug Discovery and Development

Engineered biocatalysts offer the opportunity to introduce modifications into complex lead molecules and drug candidates in a chemo-, regio- and stereoselective manner that is difficult to accomplish using traditional synthetic organic chemistry. As candidate biocatalysts, the cytochrome P450 enzymes that metabolize drugs and other xenobiotics are amongst the most versatile agents known. Not only can they mediate an exceptional range of biotransformation reactions, but they act on an unparalleled diversity of substrates. However, this versatility comes at the cost of relatively poor catalytic efficiency and low rates of coupling of cofactor consumption to product formation. Directed evolution is being used to redefine the substrate specificity of P450 enzymes while at the same time improving their efficiency, thermostability and other properties. This review will outline the key successes with bacterial P450s used as biocatalysts, examine the studies done to date with mammalian forms, and assess the prospects for exploiting xenobiotic-metabolizing P450s for applications in medicinal chemistry.