Alternate Heme Ligation Steers Activity and Selectivity in Engineered Cytochrome P450-Catalyzed Carbene-Transfer Reactions

• Published in: Journal of the American Chemical Society Vol. 140; no. 48; pp. 16402 - 16407
• Main Authors: Chen, Kai, Zhang, Shuo-Qing, Brandenberg, Oliver F, Hong, Xin, Arnold, Frances H
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 05.12.2018; Amer Chemical Soc
• Subjects: carbenes; catalytic activity; chemical bonding; Chemistry; Chemistry, Multidisciplinary; cytochrome P-450; enzymes; heme; lactones; ligands; olefin; Physical Sciences; Science & Technology; steers; stereoselectivity; IRON PORPHYRIN CARBENES; SUBSTITUENT; INSERTION; ENANTIOSELECTIVE S-H; CONSTRUCTION; CYCLOPROPANATION; CATALYZED INTERMOLECULAR REACTIONS; LACTONE BUILDING-BLOCKS; BIOCATALYTIC PREPARATION
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.8b09613

We report a biocatalytic platform of engineered cytochrome P450 enzymes to carry out carbene-transfer reactions using a lactone-based carbene precursor. By simply altering the heme-ligating residue, we obtained two enzymes that catalyze olefin cyclopropanation (Ser) or S–H bond insertion (Cys). Both enzymes exhibit high catalytic efficiency and stereo­selectivity, thus enabling facile access to structurally diverse spiro[2.4]­lactones and α-thio-γ-lactones. Computational studies revealed the mechanism of carbene S–H insertion and explain how the axial ligand controls reactivity and selectivity. This work expands the catalytic repertoire of heme­proteins and offers insights into how these enzymes can be tuned for new chemistry.