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

Jyoti Singh, Benjamin Thoma, Daniel Whitaker, Max Satterly Webley, Yuan Yao and Matthew W. Powner ()
Additional contact information
Jyoti Singh: University College London
Benjamin Thoma: University College London
Daniel Whitaker: University College London
Max Satterly Webley: University College London
Yuan Yao: University College London
Matthew W. Powner: University College London

Nature, 2025, vol. 644, issue 8078, 933-944

Abstract: 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 water3–5. 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-09388-y Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:644:y:2025:i:8078:d:10.1038_s41586-025-09388-y

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-09388-y

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().