The cytochrome P450 superfamily catalyzes regio- and stereoselective functionalization of unactivated C-H bonds in a wide range of substrates. These heme thiolate enzymes activate molecular dioxygen at their active site using two electrons provided by a reductase domain and two protons. In order to harness the synthetic potential of P450 enzymes upon visible light excitation, we have developed hybrid P450 enzymes which contain a Ru(II)-diimine photosensitizer strategically attached to non-native cysteine residues of P450 heme domains. High photocatalytic activity (i.e. high total turnover numbers and initial reaction rates) was achieved in the hydroxylation of natural long-chain fatty acid substrates. The crystal structure of the most efficient hybrid enzyme revealed that the photosensitizer is ideally positioned to deliver electrons to the active site utilizing the natural electron transfer pathway. We will present our latest results on the next generation of hybrid enzymes with enhanced photocatalytic activity towards a wide range of non-natural substrates. Our efforts to continually optimize the light-driven P450 biocatalysts have centered around engineering the P450 heme domain using a combination of rational and directed evolution approaches as well as tuning the photochemical properties of the Ru(II) photosensitizer. We have also combined the advantages of photoredox catalysis with the hybrid enzymes in order to perform tandem C-H functionalizations upon visible light excitation.

Selective substrates C-H functionalization with light-driven P450 enzymes

253rd National Meeting (2017)

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