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.
Keywords: Drug development, cytochrome P450, directed evolution, biocatalysis, P450 BM3, high throughput screening, metabolite
identification, protein engineering.
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Published on: 02 October, 2013
Page: [2254 - 2280]