Author:

Kato N, Suzuki H, Takagi H, Asami Y, Kakeya H, Uramoto M, Usui T, Takahashi S, Sugimoto Y, Osada H.

Date: 23 March 2009

Abstract:

Missing links in the fumitremorgin biosynthetic pathway have been elucidated as 1) hydroxylation of the tryprostatin B indole ring at C-6 by FtmC, 2) C–N bond formation by FtmE to produce fumitremorgin C, and 3) the subsequent dihydroxylation of fumitremorgin C by FtmG to afford fumitremorgin B. These are also crucial processes for the inhibitory activity of fumitremorgin C against breast cancer resistance protein (BCRP).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.

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