英国牛津大学Yimon Aye等研究人员合作。绘制出活体秀丽隐杆线虫的器官特异性电亲和反应图谱。相关论文于2024年11月5日在线发表在《细胞》杂志上。

研究人员表示，接近标记技术仅限于索引局部蛋白的驻留状态。这些数据尽管具有价值，却无法揭示局部蛋白对小分子反应的敏感性。

研究人员通过展示如何在活体秀丽隐杆线虫中，定量绘制和排名特定器官的电亲和反应倾向，弥补了这一空白。使用该方法，超过70%的组织特异性反应者表现出电亲和反应性，这与组织特异性的丰度无关。

其中一个反应者，cyp-33e1（其人类和线虫同源基因均对电亲和物质具有反应）调控着依赖压力的肠道功能，尽管在所有研究的组织中其丰度表现出一致性。Cyp-33e1的局部电亲和反应性具有位点特异性，通过催化位点的半胱氨酸进行电亲和物质感应，进而在酶抑制和关键代谢物的局部生产之间进行分配。

这些代谢物控制着全局脂质的可用性，而快速的双半胱氨酸位点特异性感应则调节肠道稳态。除了揭示局部蛋白质组中的化学可操作性，器官特异性电亲和反应性图谱还揭示了，难以处理的局部代谢物信号传递和压力反应程序，这些程序在器官特异性的决策过程中发挥作用。

附：英文原文

Title: Organ-specific electrophile responsivity mapping in live C. elegans

Author: Jinmin Liu, Amogh Kulkarni, Yong-Qi Gao, Daniel A. Urul, Romain Hamelin, Balázs á. Novotny, Marcus J.C. Long, Yimon Aye

Issue&Volume: 2024-11-05

Abstract: 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.

DOI: 10.1016/j.cell.2024.10.014

Source: https://www.cell.com/cell/abstract/S0092-8674(24)01190-5