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

研究成果: Article査読

52 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)920-928
ページ数9
ジャーナルChemBioChem
10
5
DOI
出版ステータスPublished - 2009 3 23

ASJC Scopus subject areas

  • 生化学
  • 分子医療
  • 分子生物学
  • 有機化学

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