Lin Shixian, Yang Xiaoyu, Jia Shang, Weeks Amy M, Hornsby Michael, Lee Peter S, Nichiporuk Rita V, Iavarone Anthony T, Wells James A, Toste F Dean, Chang Christopher J
Department of Chemistry, University of California, Berkeley, CA, USA.
School of Physical Science and Technology, ShanghaiTech University, Shanghai, China.
Science. 2017 Feb 10;355(6325):597-602. doi: 10.1126/science.aal3316.
Cysteine can be specifically functionalized by a myriad of acid-base conjugation strategies for applications ranging from probing protein function to antibody-drug conjugates and proteomics. In contrast, selective ligation to the other sulfur-containing amino acid, methionine, has been precluded by its intrinsically weaker nucleophilicity. Here, we report a strategy for chemoselective methionine bioconjugation through redox reactivity, using oxaziridine-based reagents to achieve highly selective, rapid, and robust methionine labeling under a range of biocompatible reaction conditions. We highlight the broad utility of this conjugation method to enable precise addition of payloads to proteins, synthesis of antibody-drug conjugates, and identification of hyperreactive methionine residues in whole proteomes.
半胱氨酸可通过多种酸碱共轭策略进行特异性功能化，其应用范围涵盖从探测蛋白质功能到抗体 - 药物偶联物及蛋白质组学等领域。相比之下，由于甲硫氨酸本质上亲核性较弱，因此一直无法实现与另一种含硫氨基酸（甲硫氨酸）的选择性连接。在此，我们报告了一种通过氧化还原反应性实现甲硫氨酸化学选择性生物共轭的策略，使用基于氮杂环丙烷的试剂，在一系列生物相容性反应条件下实现高度选择性、快速且稳定的甲硫氨酸标记。我们强调了这种共轭方法的广泛实用性，它能够精确地将有效载荷添加到蛋白质上、合成抗体 - 药物偶联物以及鉴定完整蛋白质组中高反应性的甲硫氨酸残基。
