Complexity generation in fungal polyketide biosynthesis: a spirocycle-forming P450 in the concise pathway to the antifungal drug griseofulvin

Details

• Alternative Title:
  ACS Chem Biol
• Personal Author:
  Cacho, Ralph A. ; Chooi, Yit-Heng ; Zhou, Hui ; Tang, Yi
• Description:
  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.
• Subjects:
  Antifungal Agents Benzophenones Chromatography, High Pressure Liquid Cytochrome P-450 Enzyme System Griseofulvin Malonyl Coenzyme A Molecular Structure Oxidation-Reduction Phloroglucinol Resorcinols Stereoisomerism

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• Keywords:
  Antifungal Cytochrome P450 Polyketides
• Source:
  ACS Chem Biol. 8(10):2322-2330
• Pubmed ID:
  23978092
• Pubmed Central ID:
  PMC3821396
• Document Type:
  Journal Article
• Funding:
  1R01GM085128/GM/NIGMS NIH HHSUnited States/ ; GM-0846/GM/NIGMS NIH HHSUnited States/ ; T32 GM008496/GM/NIGMS NIH HHSUnited States/ ; R01 GM085128/GM/NIGMS NIH HHSUnited States/ ; DP1 GM106413/GM/NIGMS NIH HHSUnited States/ ; 1DP1GM106401/DP/NCCDPHP CDC HHSUnited States/
• Volume:
  8
• Issue:
  10
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:6bf6374d5a90134bf55dfd630533af3bba3f37971f7f3131ef05b1e8f24a0dbd
• Download URL:
  https://stacks.cdc.gov/view/cdc/29769/cdc_29769_DS1.pdf
• File Type:
  [PDF - 2.26 MB ]