The design and engineering of protein catalysts that carry out rare or non-natural chemistry remains a challenging contemporary goal. However, enzymes are inherently limited by their chemical composition, i.e. the reagent pool that exists in nature and the amino acids and cofactors that form their physical and catalytic core. Because of this limitation, the majority of chemical transformations developed by synthetic chemists remain, at least to our knowledge, biologically inaccessible. Biological cofactors and prosthetic groups, including heme, provide a convenient means for natural proteins to increase their range 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 non-natural reagents we have been able to demonstrate that a variety of natural enzyme scaffolds are capable of carrying out reactions, including the carbene-mediated cyclopropanation of olefins, not previously observed in the natural world. Moreover, as adaptable, genetically encoded systems, the activity and product regio- and stereochemical profiles of these catalysts can be tuned in a systematic fashion by evolution. We have gone on to show that cytochrome P450s can be adapted for the incorporation of alternative metalloporphyrin scaffolds. By combining non-natural cofactor engineering with an increase in reagent diversity, we are generating orthogonal protein systems that deliver function not readily available in nature.<br/>

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

249th National Meeting (2015)

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