Expanding chemistry of cytochrome P450 BM3 through directed evolution
Pedro Coelho, Ryan Lauchli, John McIntosh, Fei Sun, Jane Wang
Cytochrome P450 enzymes are nature's premier oxidation catalysts. These heme iron-containing enzymes are found in all domains of life and catalyze diverse reactions in their native contexts, including hydroxylation (of aromatic and aliphatic carbons), epoxidation, as well as heteroatom oxidation and C-C bond formation. Cytochrome P450s are used by microbes and plants in the synthesis of natural products, where they can insert hydroxyl groups into the unactivated C-H bonds that abound in terpene and polyketide scaffolds, leading to the synthesis of structurally complex antibiotics and signaling molecules. In animals, cytochrome P450s play important roles in the detoxification of xenobiotics, as well as in the synthesis of hormones and pheromones.
Given the highly diverse and useful suite of reactions catalyzed by P450s in nature, we envision a prominent role for these catalysts in synthetic chemistry. However, most cytochrome P450 enzymes are difficult to handle: they are membrane-associated, expressed at low levels in heterologous hosts, and require specific reductase enzymes in order to proceed through the catalytic cycle. Furthermore, the substrates for many P450s are unknown.
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