Engineering Cytochrome P450 for Cyclopropanation

The ability to genetically encode catalysts for non-natural chemical reactions will open new routes to sustainable production of chemicals. In nature, cytochome P450 catalyzes the oxidation of organic substrates with oxygen to produce epoxides and alcohols. This transformation proceeds through an iron-oxene complex (Compound I), which is generated in the presence of NAD(P)H and molecular oxygen. Inspired by this catalytic cycle, we hypothesized that a similar process could be used to generate an iron-carbenoid specie from diazo compounds that could enable olefin cyclopropanation. Toward this end, we have been able to evolve a unique serine-heme ligated cytochrome “P411” that catalyzes formal carbene transfers from diazoesters to olefins with very high efficiency