Kato Naoki, Suzuki Hirokazu, Takagi Hiroshi, Asami Yukihiro, Kakeya Hideaki, Uramoto Masakazu, Usui Takeo, Takahashi Shunji, Sugimoto Yoshikazu, Osada Hiroyuki
Chemical Biology Department, Advanced Science Institute, RIKEN, Wako, Saitama 351-0198, Japan.
Chembiochem. 2009 Mar 23;10(5):920-8. doi: 10.1002/cbic.200800787.
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.
烟曲霉毒素C是烟曲霉产生的一种二酮哌嗪霉菌毒素，是乳腺癌耐药蛋白（BCRP）的一种强效特异性抑制剂。阐明烟曲霉毒素C的生物合成途径为新药设计提供了一种策略。基于与ftm基因簇相关的代谢产物进行的构效关系研究表明，对BCRP产生抑制活性最为关键的过程是环化形成烟曲霉毒素C。为了确定参与环化反应的基因，对ftm簇中的候选基因进行了靶向基因失活。对基因破坏体的分析使我们能够确定ftmE，即该簇中的细胞色素P450基因之一，是烟曲霉毒素生物合成关键步骤的负责基因。此外，我们还证明了另外两个细胞色素P450基因ftmC和ftmG分别参与吲哚环的羟基化和烟曲霉毒素C的连续羟基化。
