伦敦大学学院Matthew W. Powner研究团队近日取得一项新成果。经过不懈努力，他们研制了硫酯介导的RNA氨基酰化和水中肽基RNA合成。相关论文于2025年8月27日发表于国际顶尖学术期刊《自然》杂志上。

在这里，该课题组人员证明（生物）氨基酰基硫醇(1)选择性地与胺亲核试剂上的RNA二醇反应，促进氨基酰化而不是非编码肽键的形成。广泛的侧链范围，包括Ala， Arg, Asp, Glu, Gln, Gly, His, Leu, Lys, Met, Phe, Pro,Ser和Val，并且Arg氨基酰化被前所未有的侧链亲核催化增强。双相形成指导RNA的化学选择性2',3' -氨基酰化。

研究组证明了益生元腈、N-羧基氢化物和氨基酸酸酐，以及生物氨基酰基腺苷酸，都与硫醇（包括辅酶A和M）在水中选择性地生成氨基酰基硫醇(1)。最后，课题组研究人员证明了从硫酯活化到硫酸活化的转换逆转了二醇/胺的选择性，促进了肽的高收率合成。在中性pH值的水中观察到肽基RNA的两步一锅化学控制形成。这些结果表明，在蛋白质乙酰化合成酶进化之前，巯基辅助因子在RNA氨基酰化中起着重要作用。

研究人员表示，为了协调核糖体肽的合成，转移RNA（tRNAs）必须在其2',3' -二醇基团上被活化的氨基酸氨基化，因此RNA在水中的选择性氨基化是解释蛋白质生物合成起源的关键挑战。到目前为止，还没有化学方法可以有效地、选择性地对RNA-2',3' -二醇进行氨基化，使其具有水中蛋白质氨基酸的宽度。

附：英文原文

Title: Thioester-mediated RNA aminoacylation and peptidyl-RNA synthesis in water

Author: Singh, Jyoti, Thoma, Benjamin, Whitaker, Daniel, Satterly Webley, Max, Yao, Yuan, Powner, Matthew W.

Issue&Volume: 2025-08-27

Abstract: To orchestrate ribosomal peptide synthesis, transfer RNAs (tRNAs) must be aminoacylated, with activated amino acids, at their 2′,3′-diol moiety1,2, and so the selective aminoacylation of RNA in water is a key challenge that must be resolved to explain the origin of protein biosynthesis. So far, there have been no chemical methods to effectively and selectively aminoacylate RNA-2′,3′-diols with the breadth of proteinogenic amino acids in water3,4,5. Here we demonstrate that (biological) aminoacyl-thiols (1) react selectively with RNA diols over amine nucleophiles, promoting aminoacylation over adventitious (non-coded) peptide bond formation. Broad side-chain scope is demonstrated, including Ala, Arg, Asp, Glu, Gln, Gly, His, Leu, Lys, Met, Phe, Pro, Ser and Val, and Arg aminoacylation is enhanced by unprecedented side-chain nucleophilic catalysis. Duplex formation directs chemoselective 2′,3′-aminoacylation of RNA. We demonstrate that prebiotic nitriles, N-carboxyanhydrides and amino acid anhydrides, as well as biological aminoacyl-adenylates, all react with thiols (including coenzymes A and M) to selectively yield aminoacyl-thiols (1) in water. Finally, we demonstrate that the switch from thioester to thioacid activation inverts diol/amine selectivity, promoting peptide synthesis in excellent yield. Two-step, one-pot, chemically controlled formation of peptidyl-RNA is observed in water at neutral pH. Our results indicate an important role for thiol cofactors in RNA aminoacylation before the evolution of proteinaceous synthetase enzymes.

DOI: 10.1038/s41586-025-09388-y

Source: https://www.nature.com/articles/s41586-025-09388-y