Identification of cytochrome P450s required for fumitremorgin biosynthesis in Aspergillus fumigatus

Naoki Kato, Hirokazu Suzuki, Hiroshi Takagi, Yukihiro Asami, Hideaki Kakeya, Masakazu Uramoto, Takeo Usui, Shunji Takahashi, Yoshikazu Sugimoto, Hiroyuki Osada

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Fumitremorgin C, a diketopiperazine mycotoxin produced by Aspergillus fumigatus, is a potent and specific inhibitor of breast cancer resistance protein (BCRP). Elucidation of the fumitremorgin C biosynthetic pathway provides a strategy for new drug design. A structure-activity relationship study based on metabolites related to the ftm gene cluster revealed that the process most crucial for inhibitory activity against BCRP was cyclization to form fumitremorgin C. To determine the gene involved in the cyclization reaction, targeted gene inactivation was performed with candidate genes in the ftm cluster. Analysis of the gene disruptants allowed us to identify ftmE, one of the cytochrome P450 genes in the cluster, as the gene responsible for the key step in fumitremorgin biosynthesis. Additionally, we demonstrated that the other two cytochrome P450 genes, ftmC and ftmG, were involved in hydroxylation of the indole ring and successive hydroxylation of fumitremorgin C, respectively.

Original languageEnglish
Pages (from-to)920-928
Number of pages9
JournalChemBioChem
Volume10
Issue number5
DOIs
Publication statusPublished - 2009 Mar 23

Keywords

  • Aspergillus fumigatus
  • Biosynthesis
  • Cytochrome P450
  • Fumitremorgins
  • Natural products

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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  • Cite this

    Kato, N., Suzuki, H., Takagi, H., Asami, Y., Kakeya, H., Uramoto, M., Usui, T., Takahashi, S., Sugimoto, Y., & Osada, H. (2009). Identification of cytochrome P450s required for fumitremorgin biosynthesis in Aspergillus fumigatus. ChemBioChem, 10(5), 920-928. https://doi.org/10.1002/cbic.200800787