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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.

SUBMITTER: Grandner JM

PROVIDER: S-EPMC5425163 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Grandner Jessica M JM Cacho Ralph A RA Tang Yi Y Houk K N KN

ACS catalysis 20160531 7

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. C ...[more]

PMID: 28503354

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