Mechanism of the P450-Catalyzed Oxidative Cyclization in the Biosynthesis of Griseofulvin

Abstract

Griseofulvin is an anti-fungal agent which has recently been determined to have potential anti-viral and anti-cancer applications. The role of specific enzymes involved in the biosynthesis of this natural product has previously been determined, but the mechanism by which a p450, GsfF, catalyzes the key oxidative cyclization of griseophenone B remains unknown. Using density functional theory (DFT), we have determined the mechanism of this oxidation that forms the oxa-spiro core of griseofulvin. Computations show GsfF preferentially performs two sequential phenolic O-H abstractions rather than epoxidation to form an arene oxide intermediate. This conclusion is supported by experimental kinetic isotope effects.