美国加州大学Chang, Christopher J.团队报道了氧化环化试剂揭示色氨酸阳离子-π相互作用。相关研究成果发表在2024年3月6日出版的《自然》。

蛋白质上氨基酸的选择性共价修饰方法可以实现，从蛋白质功能的探针和调节剂到蛋白质组的多种应用。半胱氨酸和赖氨酸残基由于其高度亲核性，是通过酸碱反应进行蛋白质生物偶联化学的最常见的连接点。

该文中，研究人员报道了一种基于氧化还原的策略，用于色氨酸（最稀有的氨基酸）的生物偶联，使用氧氮环丙烷试剂模拟吲哚类生物碱生物合成途径中的氧化环化反应，以实现高效和特异的色氨酸标记。

研究人员建立了这种方法的广泛用途，称为环化色氨酸化学连接（Trp-CLiC），用于选择性地将有效载荷附加到肽和蛋白质上的色氨酸残基上，其反应速率可与传统的点击反应相媲美，并能够对整个蛋白质组中的高反应性色氨酸位点进行全局分析。

值得注意的是，这些试剂揭示了参与阳离子-π相互作用的色氨酸残基的系统图谱，包括可以调节蛋白质介导的相分离过程的功能位点。

附：英文原文

Title: Oxidative cyclization reagents reveal tryptophan cation–π interactions

Author: Xie, Xiao, Moon, Patrick J., Crossley, Steven W. M., Bischoff, Amanda J., He, Dan, Li, Gen, Dao, Nam, Gonzalez-Valero, Angel, Reeves, Audrey G., McKenna, Jeffrey M., Elledge, Susanna K., Wells, James A., Toste, F. Dean, Chang, Christopher J.

Issue&Volume: 2024-03-06

Abstract: Methods for selective covalent modification of amino acids on proteins can enable a diverse array of applications, spanning probes and modulators of protein function to proteomics1,2,3. Owing to their high nucleophilicity, cysteine and lysine residues are the most common points of attachment for protein bioconjugation chemistry through acid–base reactivity3,4. Here we report a redox-based strategy for bioconjugation of tryptophan, the rarest amino acid, using oxaziridine reagents that mimic oxidative cyclization reactions in indole-based alkaloid biosynthetic pathways to achieve highly efficient and specific tryptophan labelling. We establish the broad use of this method, termed tryptophan chemical ligation by cyclization (Trp-CLiC), for selectively appending payloads to tryptophan residues on peptides and proteins with reaction rates that rival traditional click reactions and enabling global profiling of hyper-reactive tryptophan sites across whole proteomes. Notably, these reagents reveal a systematic map of tryptophan residues that participate in cation–π interactions, including functional sites that can regulate protein-mediated phase-separation processes.

DOI: 10.1038/s41586-024-07140-6

Source: https://www.nature.com/articles/s41586-024-07140-6