Identification of Cytochrome P450s Required for Fumitremorgin Biosynthesis in Aspergillus fumigatus
Identification of Cytochrome P450s Required for Fumitremorgin Biosynthesis in Aspergillus fumigatus
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DOI：
10.1002/cbic.200800787
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发表时间：
2009-03-23
期刊：
影响因子：
3.2
通讯作者：
Osada, Hiroyuki
中科院分区：
文献类型：
--
作者：
Kato, Naoki;Suzuki, Hirokazu;Osada, Hiroyuki
烟曲霉菌毒素Fumitremorgin C是由烟曲霉菌产生的一种二酮基哌嗪类真菌毒素，是乳腺癌耐药蛋白(BCRP)的一种有效和特异的抑制剂。Fumitremorgin C生物合成途径的阐明为新药设计提供了策略。基于FTM基因簇相关代谢物的构效关系研究表明，对BCRP的抑制活性最关键的过程是环化形成Fumitremorgin C。为了确定参与环化反应的基因，对FTM基因簇中的候选基因进行了靶向基因失活。对基因干扰物的分析使我们能够确定ftmE是该簇中的细胞色素P450基因之一，是负责Fumitremorgin生物合成的关键步骤的基因。此外，我们还证明了另外两个细胞色素P450基因，ftmC和ftmg，分别参与了吲哚环的羟化和烟曲霉素C的连续羟化。
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.