New recipes for biocatalysis: expanding the cytochrome P450 reaction landscape for non-natural chemistry

The design and engineering of protein catalysts that carry out rare or non-natural chemistry remains a challenging contemporary goal. Biological cofactors and prosthetic groups, including heme, provide a convenient means for natural proteins to increase their range of chemical transformations. For example, the heme group of cytochrome P450s catalyzes myriad oxidative transformations in the presence of oxygen as a reagent. Synthetic catalysts, similar to heme, demonstrate a wealth of chemical transformations, including metallocarbene and -nitrene insertion reactions, through mechanisms similar to native P450 catalysis; however, these reactions do not exist in biology due to the lack of the necessary ingredients in the cell or surrounding environment. By supplementing cytochrome P450s with diazoacetates we have shown that a large number of scaffolds from this diverse enzyme family are capable of carrying out the carbene-mediated cyclopropanation of olefins, including natural product-like molecules. Moreover, as adaptable, genetically encoded systems, the activity and product regio- and stereochemical profiles of these catalysts can be tuned by mutation.