对三联苯是一类具有广泛生物活性的天然产物，主要分布于真菌，在链霉菌中也有少数报道。尽管这类化合物的发现很早，但直到最近才有其生物合成的少量报道，除核心骨架的缩合外，其余步骤的合成机制尚不完全明确。前期，我们从海洋链霉菌LZ35菌株中分离获得了一类新颖的对三联苯糖苷echosides，并通过生物信息学分析和基因敲除定位了其生物合成基因簇，为进一步阐明对三联苯类化合物的生物合成奠定了基础。本申请项目拟通过体内敲除、回补、异源表达和体外酶学实验解析echosides的苯环芳香化、甲基化和糖基化机制，试图最终阐明echosides的生物合成途径。同时，我们还尝试进一步通过改造苯醌合成酶的底物特异性合成新颖的对三联苯衍生物。

p-Terphenyls with significant biological activities are a family of natural products mainly produced by fungi and rarely isolated from Streptomyces. Although p-terphenyls have been isolated for a long time, the biosynthetic mechnism of them is still unclear to a large extend. Recently, we identified several p-terphenyls (echosides) from marine-derived Streptomyces sp. LZ35, which provides a good opportunity to carry out the biosynthetic study on these natural products. The biosynthetic gene cluster of echosides has been identified in the genome of LZ35 by gene knockout experiment. In this proposal, we are planning to apply gene knockout, heterologous expression and in vitro biochemical characterization of key enzymes to dissect the biosynthesis of echosides, including aromatization of B-ring, methylation and glycosylation, and to elucidate the biosynthetic pathway of echosides. Another aspect of this proposal is derivatization of p-terphenyl for more potent drug candidates by rational design of quinone synthetase.