Deep Interrogation of Metabolism Using a Pathway-Targeted Click-Chemistry Approach,Journal of the American Chemical Society

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Deep Interrogation of Metabolism Using a Pathway-Targeted Click-Chemistry Approach
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-10-14 , DOI: 10.1021/jacs.0c06877
Jason S Hoki ₁ , Henry H Le ₁ , Karlie E Mellott ₁ , Ying K Zhang ₁ , Bennett W Fox ₁ , Pedro R Rodrigues ₁ , Yan Yu ₁ , Maximilian J Helf ₁ , Joshua A Baccile ₂ , Frank C Schroeder ₁

Affiliation

Untargeted metabolomics indicates that the number of unidentified small-molecule metabolites may exceed the number of protein-coding genes for many organisms, including humans, by orders of magnitude. Uncovering the underlying metabolic networks is essential for elucidating the physiological and ecological significance of these biogenic small molecules. Here we develop a click-chemistry-based enrichment strategy, DIMEN (deep interrogation of metabolism via enrichment), that we apply to investigate metabolism of the ascarosides, a family of signaling molecules in the model organism C. elegans. Using a single alkyne-modified metabolite and a solid-phase azide resin that installs a diagnostic moiety for MS/MS-based identification, DIMEN uncovered several hundred novel compounds originating from diverse biosynthetic transformations that reveal unexpected intersection with amino acid, carbohydrate, and energy metabolism. Many of the newly discovered transformations could not be identified or detected by conventional LC-MS analyses without enrichment, demonstrating the utility of DIMEN for deeply probing biochemical networks that generate extensive yet uncharacterized structure space.

中文翻译：

使用靶向通路的点击化学方法深入探究代谢

非靶向代谢组学表明，对于包括人类在内的许多生物体，未鉴定的小分子代谢物的数量可能超过蛋白质编码基因的数量数量级。揭示潜在的代谢网络对于阐明这些生物小分子的生理和生态意义至关重要。在这里，我们开发了一种基于点击化学的富集策略 DIMEN（通过富集深度询问代谢），我们将其应用于研究蛔苷的代谢，蛔苷是模式生物线虫中的一个信号分子家族。使用单一炔烃修饰的代谢物和固相叠氮化物树脂，该树脂安装了用于基于 MS/MS 的鉴定的诊断部分，DIMEN 发现了数百种源自不同生物合成转化的新化合物，这些转化揭示了与氨基酸、碳水化合物和能量代谢的意外交叉。许多新发现的转化在没有富集的情况下无法通过传统的 LC-MS 分析进行识别或检测，这证明了 DIMEN 在深入探测生化网络方面的效用，这些网络产生了广泛但未表征的结构空间。

更新日期：2020-10-14

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