2021年9月9日，美国斯克里普斯研究所Benjamin F. Cravatt研究团队在《自然—化学》杂志发表论文，报道了赖氨酸反应化学的全蛋白质组图谱。

该课题组人员报告了超过30种未知的亲氨化学类型的深入分析，这些类型极大地扩展了人类蛋白中配体赖氨酸的含量。亲氨亲电试剂表现出不同的蛋白质组学反应，从与少数赖氨酸的选择性相互作用，到一组二羧醛片段，共价小分子与赖氨酸相互作用的广泛参与被整个文库捕获。

该课题组使用这些后者“侦察”亲电试剂，在刺激条件下有效地定位原代人类免疫细胞中的配体赖氨酸。最后，课题组人员发现，亲氨基化合物通过蛋白质中赖氨酸的位点选择性修饰扰乱了多种生化功能，包括先天免疫反应涉及的蛋白质-RNA相互作用。

这些发现支持了共价化学在靶向人类蛋白质组中的功能性赖氨酸方面的广泛潜力。

据了解，化学蛋白质组学的最新进展已经开始在整体范围内描述赖氨酸的反应性和配体性。然而，只有有限的多样性的亲氨亲电试剂已被评估与赖氨酸蛋白质组相互作用。

附：英文原文

Title: A proteome-wide atlas of lysine-reactive chemistry

Author: Abbasov, Mikail E., Kavanagh, Madeline E., Ichu, Taka-Aki, Lazear, Michael R., Tao, Yongfeng, Crowley, Vincent M., am Ende, Christopher W., Hacker, Stephan M., Ho, Jordan, Dix, Melissa M., Suciu, Radu, Hayward, Matthew M., Kiessling, Laura L., Cravatt, Benjamin F.

Issue&Volume: 2021-09-09

Abstract: Recent advances in chemical proteomics have begun to characterize the reactivity and ligandability of lysines on a global scale. Yet, only a limited diversity of aminophilic electrophiles have been evaluated for interactions with the lysine proteome. Here, we report an in-depth profiling of >30 uncharted aminophilic chemotypes that greatly expands the content of ligandable lysines in human proteins. Aminophilic electrophiles showed disparate proteomic reactivities that range from selective interactions with a handful of lysines to, for a set of dicarboxaldehyde fragments, remarkably broad engagement of the covalent small-molecule–lysine interactions captured by the entire library. We used these latter ‘scout’ electrophiles to efficiently map ligandable lysines in primary human immune cells under stimulatory conditions. Finally, we show that aminophilic compounds perturb diverse biochemical functions through site-selective modification of lysines in proteins, including protein–RNA interactions implicated in innate immune responses. These findings support the broad potential of covalent chemistry for targeting functional lysines in the human proteome.

DOI: 10.1038/s41557-021-00765-4

Source: https://www.nature.com/articles/s41557-021-00765-4