Genome Mining of the Biosynthetic Gene Cluster of the Polyene Macrolide Antibiotic Tetramycin and Characterization of a P450 Monooxygenase Involved in the Hydroxylation of the Tetramycin B Polyol Segment

文献类型： 外文期刊

第一作者： Cao, Bo

作者： Cao, Bo;Yao, Fen;Zheng, Xiaoqing;Cui, Dongbing;Shao, Yucheng;Deng, Zixin;You, Delin;Cao, Bo;Yao, Fen;Zheng, Xiaoqing;Cui, Dongbing;Shao, Yucheng;Deng, Zixin;You, Delin;Zhu, Changxiong

作者机构：

关键词： Antifungal agents;Cytochrome P450 monooxygenase;Natural products;Polyene macrolide antibiotics;Polyketide synthases

期刊名称：CHEMBIOCHEM （ 影响因子：3.164； 五年影响因子：3.013 ）

ISSN：

年卷期：

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收录情况： SCI

摘要： A polyene macrolide antibiotic tetramycin biosynthetic gene cluster was identified by genome mining and isolated from Streptomyces hygrospinosus var. beijingensis. Genetic and in silico analyses gave insights into the mechanism of biosynthesis of tetramycin, and a model of the tetramycin biosynthetic pathway is proposed. Inactivation of a cytochrome P450 monooxygenase gene, tetrK, resulted in the production of a tetramycin B precursor: tetramycin A, which lacks a hydroxy group in its polyol region. TetrK was subsequently overexpressed heterologously in E. coli with a His_6 tag, and purified TetrK efficiently hydroxylated tetramycin A to afford tetramycin B. Kinetic studies revealed no inhibition of TetrK by substrate or product. Surprisingly, sequence-alignment analysis showed that TetrK, as a hydroxylase, has much higher homology with epoxidase PimD than with hydroxylases NysL and AmphL. The 3D structure of TetrK was then constructed by homology modeling with PimD as reference. Although TetrK and PimD catalyzed different chemical reactions, homology modeling indicated that they might share the same catalytic sites, despite also possessing some different sites correlated with substrate binding and substrate specificity. These findings offer good prospects for the production of improved antifungal polyene analogues.

分类号： Q7

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