title: Complexity generation in fungal polyketide biosynthesis: a spirocycle-forming P450 in the concise pathway to the antifungal drug griseofulvin.
abstract: Griseofulvin (1) is a spirocyclic fungal natural product used in treatment of fungal dermatophytes. Formation of the spirocycle, or the grisan scaffold, from a benzophenone precursor is critical for the activity of 1. In this study, we have systematically characterized each of the biosynthetic enzymes related to the biogenesis of 1, including the characterization of a new polyketide synthase GsfA that synthesizes the benzophenone precursor and a cytochrome P450 GsfF that performs oxidative coupling between the orcinol and the phloroglucinol rings to yield the grisan structure. Notably, the finding of GsfF is in sharp contrast to the copper-dependent dihydrogeodin oxidase that performs a similar reaction in the geodin biosynthetic pathway. The biosynthetic knowledge enabled the in vitro total biosynthesis of 1 from malonyl-CoA using all purified enzyme components. This work therefore completely maps out the previously unresolved enzymology of the biosynthesis of a therapeutically relevant natural product.
authors: Department of Chemical and Biomolecular Engineering, University of California, Los Angeles , 420 Westwood Plaza, Los Angeles, California 90095, United States.
authors: Ralph A
authors: RA
authors: Cacho
authors: Yit-Heng
authors: YH
authors: Chooi
authors: Hui
authors: H
authors: Zhou
authors: Yi
authors: Y
authors: Tang
mesh_terms: D000935:Antifungal Agents / Q000378:metabolism*; D001577:Benzophenones / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006118:Griseofulvin / Q000096:biosynthesis*; D008316:Malonyl Coenzyme A / Q000378:metabolism; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010696:Phloroglucinol / Q000737:chemistry; D012118:Resorcinols / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000935:Antifungal Agents; D001577:Benzophenones; D012118:Resorcinols; D006118:Griseofulvin; D008316:Malonyl Coenzyme A; C005282:orcinol; C047723:benzophenone; D003577:Cytochrome P-450 Enzyme System; D010696:Phloroglucinol
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