Metabolomic “Dark Matter” Dependent on Peroxisomal β‑Oxidation in <i>Caenorhabditis elegans</i>

Peroxisomal β-oxidation (pβo) is a highly conserved fat metabolism pathway involved in the biosynthesis of diverse signaling molecules in animals and plants. In Caenorhabditis elegans, pβo is required for the biosynthesis of the ascarosides, signaling molecules that control development, lifespan, and behavior in this model organism. Via comparative mass spectrometric analysis of pβo mutants and wildtype, we show that pβo in C. elegans and the satellite model P. pacificus contributes to life stage-specific biosynthesis of several hundred previously unknown metabolites. The pβo-dependent portion of the metabolome is unexpectedly diverse, e.g., intersecting with nucleoside and neurotransmitter metabolism. Cell type-specific restoration of pβo in pβo-defective mutants further revealed that pβo-dependent submetabolomes differ between tissues. These results suggest that interactions of fat, nucleoside, and other primary metabolism pathways can generate structural diversity reminiscent of that arising from combinatorial strategies in microbial natural product biosynthesis.过氧化物酶体β氧化（Peroxisomal β-oxidation，简称pβo）是一条高度保守的脂肪代谢通路，参与动植物体内多种信号分子的生物合成。在秀丽隐杆线虫（Caenorhabditis elegans）中，pβo是阿斯卡罗苷（ascarosides）生物合成的必需通路，而该类信号分子可调控这一模式生物的发育、寿命与行为。本研究通过对pβo突变体与野生型开展对比质谱分析，证实秀丽隐杆线虫与卫星模式生物太平洋杆线虫（Pristionchus pacificus，简称P. pacificus）体内的pβo参与了数百种此前未被发现的代谢物的发育阶段特异性生物合成。pβo依赖的代谢组组分呈现出意想不到的多样性，例如与核苷代谢及神经递质代谢存在交叉互作。在pβo缺陷型突变体中进行细胞类型特异性的pβo恢复实验，进一步揭示了pβo依赖的亚代谢组在不同组织间存在显著差异。上述结果表明，脂肪代谢、核苷代谢与其他初级代谢通路之间的互作，可产生结构多样性，这与微生物天然产物生物合成中组合策略所催生的多样性具有相似性。