Directed Evolution of P450 BM3 towards Functionalization of Aromatic O-Heterocycles
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Aromatic oxygen-containing heterocycles are significantly abundant in nature as they are present in vitamins, hormones, antibiotics, sugars, pigments, and antioxidants (e.g., vitamin E, coumarin, flavonoids, and isoflavonoids) and are involved in a variety of fundamental biological functions. These heterocycles and their derivatives are, in most cases, synthesized and functionalized by the traditional chemical route to serve as building blocks for synthetic drugs, pesticides, dyes, and plastics. By the use of engineered cytochrome P450 monooxygenase 3 from Bacillus megaterium one can functionalize these heterocycles with high chemo-, regio-, and/or enantioselectivity for the production of high-value compounds such pharmaceuticals. Screening of mutant libraries in a KnowVolution-like approach was used to identify the key position 255, which significantly improved the hydroxylation activity towards benzo-1,4-dioxane, phtalan, isochroman, benzofuran, 2,3-dihydrobenzofuran, and dibenzofuran. The improvement observed in P450 BM3 R255G and R255L provides useful enzymatic routes to produce pharmaceutical precursors in a selective and environmentally friendly way via late-stage hydroxylation.
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Santos, G. D. A., Dhoke, G. V., Davari, M. D., Ruff, A. J., & Schwaneberg, U.; Directed Evolution of P450 BM3 towards Functionalization of Aromatic O-Heterocycles; Int. J. Mol. Sci., 2019