Identification of cytochrome P450s required for fumitremorgin biosynthesis in Aspergillus fumigatus.
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.
Kato
Naoki
N
Chemical Biology Department, Advanced Science Institute, RIKEN, Wako, Saitama 351-0198, Japan.
Suzuki
Hirokazu
H
Takagi
Hiroshi
H
Asami
Yukihiro
Y
Kakeya
Hideaki
H
Uramoto
Masakazu
M
Usui
Takeo
T
Takahashi
Shunji
S
Sugimoto
Yoshikazu
Y
Osada
Hiroyuki
H
D000470:Alkaloids / Q000737:chemistry; D000818:Animals; D001232:Aspergillus fumigatus / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007211:Indoles / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D005810:Multigene Family; D010879:Piperazines / Q000737:chemistry; D013141:Spiro Compounds / Q000737:chemistry
D000470:Alkaloids; D007211:Indoles; D010879:Piperazines; D013141:Spiro Compounds; D003577:Cytochrome P-450 Enzyme System; C010522:tryptoquivaline