近日，中国科学院上海药物研究所黄蔚团队实现了通过光催化策略对肽进行生物启发的蛋氨酸选择性脱硫编辑。2025年5月5日，《美国化学会志》发表了这项成果。

S-腺苷甲硫氨酸（SAM）经常作为酶的辅因子或前体，在生物系统中引发一系列自由基反应。与传统的5′-脱氧腺苷（dAdo）自由基途径不同，该途径通过SAM的S-C（5′）键的均裂来进行，Dph2酶通过破坏S-C（γ）键提供了一种替代的3-氨基-3-羧基丙基（ACP）自由基通路。受这种独特的键断裂模式的启发，研究组开发了一种化学诱导途径，在蛋氨酸基锍上产生ACP型自由基中间体。该策略提出了一种新的蛋氨酸修饰脱硫共轭模式，与之前共轭到硫原子或蛋氨酸相邻甲基上的方法不同。 

该策略的多功能性通过各种肽的有效功能化和肽大环化得到了证明。密度泛函理论（DFT）计算为这种脱硫反应的机理提供了进一步的见解，解释了蛋氨酸基锍的S-C（γ）键均裂的特殊选择性。这种新型脱硫策略的成功实施代表了对基于锍的分子内自由基取代反应的理解取得了重大进展，并为生物分子的功能化提供了新的机会，从而促进了跨学科研究的进展。

附：英文原文

Title: Bioinspired Methionine-Selective Desulfurization Editing of Peptides via the Photocatalysis Strategy

Author: Yue Zhang, Huixin Yu, Feng Tang, Feng-Hua Zhang, Meihui Zhang, Jinhua Dong, Jianwei Zhao, Wei Huang, Bo Liu

Issue&Volume: May 5, 2025

Abstract: S-Adenosylmethionine (SAM) frequently functions as a cofactor or precursor for enzymes, initiating an array of radical reactions in biological systems. In contrast with the conventional 5′-deoxyadenosyl (dAdo) radical pathway, which proceeds via homolytic cleavage of the S–C(5′) bond of SAM, the Dph2 enzyme provides an alternative 3-amino-3-carboxypropyl (ACP) radical pathway through breaking the S–C(γ) bond. Inspired by this distinctive bond cleavage mode, we have developed a chemically induced pathway to generate an ACP-type radical intermediate on methionine-based sulfonium. This strategy presents a novel desulfurization conjugation mode for methionine modification, diverging from previous approaches that conjugate onto the sulfur atom or the adjacent methyl group of methionine. The versatility of this strategy is demonstrated by the efficient functionalization of various peptides and peptide macrocyclizations. Density Functional Theory (DFT) calculations provide further insights into the mechanism of this desulfurization reaction, explaining the exceptional selectivity of homolytic cleavage of the S–C(γ) bond of methionine-based sulfonium. The successful implementation of this novel desulfurization strategy represents a substantial advancement in the understanding of sulfonium-based intramolecular radical substitution reactions and provides new opportunities for the functionalization of biomolecules, thereby fostering progress in interdisciplinary research.

DOI: 10.1021/jacs.5c02226

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.5c02226