Proximity labeling technologies are limited to indexing localized protein residents. Such data—although valuable—cannot inform on small-molecule responsivity of local residents. We here bridge this gap by demonstrating in live C. elegans how electrophile-sensing propensity in specific organs can be quantitatively mapped and ranked. Using this method, >70% of tissue-specific responders exhibit electrophile responsivity, independent of tissue-specific abundance. One responder, cyp-33e1—for which both human and worm orthologs are electrophile responsive—marshals stress-dependent gut functions, despite manifesting uniform abundance across all tissues studied. Cyp-33e1’s localized electrophile responsivity operates site specifically, triggering multifaceted responses: electrophile sensing through the catalytic-site cysteine results in partitioning between enzyme inhibition and localized production of a critical metabolite that governs global lipid availability, whereas rapid dual-cysteine site-specific sensing modulates gut homeostasis. Beyond pinpointing chemical actionability within local proteomes, organ-specific electrophile responsivity mapping illuminates otherwise intractable locale-specific metabolite signaling and stress response programs influencing organ-specific decision-making.

中文翻译：

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活秀丽隐杆线虫中的器官特异性亲电反应性映射


邻近标记技术仅限于对定位的蛋白质居民进行索引。这些数据虽然很有价值，但无法了解当地居民的小分子反应性。我们在这里通过在活 的秀丽隐杆线虫中展示如何定量映射和排序特定器官中的亲电感应倾向来弥合这一差距。使用这种方法，>70% 的组织特异性反应者表现出亲电反应性，与组织特异性丰度无关。一个响应者 cyp-33e1 — 人类和蠕虫直系同源物都具有亲电反应性 — 尽管在所有研究组织中表现出均匀的丰度，但它组织了依赖于压力的肠道功能。Cyp-33e1 的局部亲电反应性专门作用于位点，触发多方面的反应：通过催化位点半胱氨酸的亲电感应导致酶抑制和控制整体脂质可用性的关键代谢物的局部产生之间的分配，而快速的双半胱氨酸位点特异性感应调节肠道稳态。除了确定局部蛋白质组内的化学可操作性外，器官特异性亲电反应性映射还阐明了影响器官特异性决策的棘手位置特异性代谢物信号传导和应激反应程序。