Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA.
Nat Chem Biol. 2023 Jun;19(6):676-686. doi: 10.1038/s41589-023-01301-w. Epub 2023 Apr 6.
Recent studies have revealed that Caenorhabditis elegans and other nematodes repurpose products from biochemical degradation pathways for the combinatorial assembly of complex modular structures that serve diverse signaling functions. Building blocks from neurotransmitter, amino acid, nucleoside and fatty acid metabolism are attached to scaffolds based on the dideoxyhexose ascarylose or glucose, resulting in hundreds of modular ascarosides and glucosides. Genome-wide association studies have identified carboxylesterases as the key enzymes mediating modular assembly, enabling rapid compound discovery via untargeted metabolomics and suggesting that modular metabolite biosynthesis originates from the 'hijacking' of conserved detoxification mechanisms. Modular metabolites thus represent a distinct biosynthetic strategy for generating structural and functional diversity in nematodes, complementing the primarily polyketide synthase- and nonribosomal peptide synthetase-derived universe of microbial natural products. Although many aspects of modular metabolite biosynthesis and function remain to be elucidated, their identification demonstrates how phenotype-driven compound discovery, untargeted metabolomics and genomic approaches can synergize to facilitate the annotation of metabolic dark matter.
最近的研究表明，秀丽隐杆线虫和其他线虫重新利用生化降解途径的产物，用于组合装配具有多种信号功能的复杂模块结构。来自神经递质、氨基酸、核苷和脂肪酸代谢的构建块连接到基于二脱氧己糖 ascarylose 或葡萄糖的支架上，形成数百种模块化 ascaryosides 和 glucosides。全基因组关联研究已经确定羧酸酯酶是介导模块化装配的关键酶，通过非靶向代谢组学能够实现快速化合物发现，并表明模块化代谢物生物合成源自保守解毒机制的“劫持”。因此，模块化代谢物代表了线虫中产生结构和功能多样性的一种独特生物合成策略，补充了主要由聚酮合酶和非核糖体肽合成酶衍生的微生物天然产物的宇宙。尽管模块化代谢物生物合成和功能的许多方面仍有待阐明，但它们的鉴定表明，表型驱动的化合物发现、非靶向代谢组学和基因组方法如何协同作用，促进代谢暗物质的注释。
