通过光氧化还原催化的位点选择性酪氨酸生物偶联用于天然到生物正交的蛋白质转化，这一成果由美国普林斯顿大学David W. C. MacMillan课题组经过不懈努力而取得。这一研究成果发表在2021年6月28日出版的国际学术期刊《自然—化学》上。

该团队利用光氧化还原催化，开发了一种位点选择性酪氨酸生物偶联途径，该途径包含生物正交甲酰基团，随后允许从天然蛋白合成结构确定的荧光偶联物。一种水溶性光催化剂，光黄素，已经被证明可以诱导先前未报道的吩恶嗪双醛标签和单一酪氨酸位点之间通过形成共价C-N键的氧化偶联，即使是在存在多个酪氨酸侧链的情况下。

课题组证明多种天然蛋白质，包括那些含有多个酪氨酸的，可以成功地进行酪氨酸特异性和单位点选择性标记。该技术直接将醛基引入天然蛋白，使产品快速多样化，形成一系列包括炔-叠氮化物点击反应的完善生物正交功能化方案。

据介绍，合成修饰蛋白质在药物和材料中的日益流行，暴露了对具有高位置选择性的化学修饰的有效策略的需求。虽然基因工程可以将非天然氨基酸引入重组蛋白中，但野生型蛋白的区域选择性化学修饰仍然是一个挑战。

附：英文原文

Title: Site-selective tyrosine bioconjugation via photoredox catalysis for native-to-bioorthogonal protein transformation

Author: Beryl X. Li, Daniel K. Kim, Steven Bloom, Richard Y.-C. Huang, Jennifer X. Qiao, William R. Ewing, Daniel G. Oblinsky, Gregory D. Scholes, David W. C. MacMillan

Issue&Volume: 2021-06-28

Abstract: The growing prevalence of synthetically modified proteins in pharmaceuticals and materials has exposed the need for efficient strategies to enable chemical modifications with high site-selectivity. While genetic engineering can incorporate non-natural amino acids into recombinant proteins, regioselective chemical modification of wild-type proteins remains a challenge. Herein, we use photoredox catalysis to develop a site-selective tyrosine bioconjugation pathway that incorporates bioorthogonal formyl groups, which subsequently allows for the synthesis of structurally defined fluorescent conjugates from native proteins. A water-soluble photocatalyst, lumiflavin, has been shown to induce oxidative coupling between a previously unreported phenoxazine dialdehyde tag and a single tyrosine site, even in the presence of multiple tyrosyl side chains, through the formation of a covalent C–N bond. A variety of native proteins, including those with multiple tyrosines, can successfully undergo both tyrosine-specific and single-site-selective labelling. This technology directly introduces aldehyde moieties onto native proteins, enabling rapid product diversification using an array of well-established bioorthogonal functionalization protocols including the alkyne–azide click reaction.

DOI: 10.1038/s41557-021-00733-y

Source: https://www.nature.com/articles/s41557-021-00733-y