In the nematodesCaenorhabditis elegansandPristionchus pacificus, a modular library of small molecules control behavior, lifespan, and development. However, little is known about the final steps of their biosynthesis, in which diverse building blocks from primary metabolism are attached to glycosides of the dideoxysugar ascarylose, the ascarosides. We combine metabolomic analysis of natural isolates ofP.pacificuswith genome-wide association mapping to identify a putative carboxylesterase,Ppa-uar-1, that is required for attachment of a pyrimidine-derived moiety in the biosynthesis of ubas#1, a major dauer pheromone component. Comparative metabolomic analysis of wild-type andPpa-uar-1mutants showed thatPpa-uar-1is required specifically for the biosynthesis of ubas#1 and related metabolites. Heterologous expression ofPpa-UAR-1 inC.elegansyielded a non-endogenous ascaroside, whose structure confirmed thatPpa-uar-1is involved in modification of a specific position in ascarosides. Our study demonstrates the utility of natural variation-based approaches for uncovering biosynthetic pathways.

中文翻译：

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基因组学和代谢组学自然变异的联系揭示了线虫信息素的生物合成

在线虫Caenorhabditis elegans和Pristionchus pacificus中，小分子的模块化文库控制着行为，寿命和发育。然而，对其生物合成的最终步骤知之甚少，其中，来自初级代谢的各种结构单元都附着在双脱氧糖，天冬酰胺，a螨苷的糖苷上。我们将代谢假单胞菌天然分离物的代谢组学分析与全基因组关联映射相结合，以鉴定推定的羧酸酯酶，Ppa-uar-1，这是在嘧啶嘧啶衍生的部分连接到主要的dauer信息素ubas＃1的生物合成中所必需的零件。对野生型和Ppa-uar-1突变体进行的比较代谢组学分析表明，Ppa-uar-1是ubas＃1及其相关代谢产物生物合成所特有的。Ppa-UAR-1在C中的异源表达。elegansyielded非内生的a虫甙，其结构证实Ppa-uar-1参与了a虫甙中特定位置的修饰。我们的研究证明了基于自然变异的方法在揭示生物合成途径方面的实用性。