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

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Abstract
Griseofulvin is an antifungal agent that has recently been determined to have potential antiviral and anticancer 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 phenolic O–H abstraction over epoxidation to catalyze the oxidation.
Funding Information
  • National Institute of General Medical Sciences (1DP1GM106413, 1R01GM085128, GM097200)

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