Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 141, Issue 51, Pages 20004-20008Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.9b11097
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Funding
- Japan Society for the Promotion of Science (JSPS) [26220204]
- Human Frontier Science Program [RGP0015/2017]
- Japan Science and Technology Agency (JST) CREST for Molecular Technologies
- JSPS International Postdoctoral Fellowship [16F16033]
- Grants-in-Aid for Scientific Research [16F16033] Funding Source: KAKEN
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It has been well established that the ribosome can accept various nucleophiles on the Xacyl-tRNA in the A site during elongation, where X can be amino, N-alkyl-amino, hydroxy, and thiol groups. However, it remains elusive that the ribosome is able to accept an electrophile in the P site other than the carboxyl group during elongation. Here we report ribosomal formation of a thioamide bond in the mRNA-dependent polypeptide synthesis. In this study, amino(carbothio)-acyl-tRNA was prepared by flexizyme and used for the expression of peptides containing a thioamide bond in the nascent peptide chain. We give strong evidence that the thioamide-peptide was formed but accompanied by the amide counterpart due to rapid carbo(S-to-O) exchange during the preparation of amino(carbothio)acyl-tRNA. We also demonstrate the ribosomal formation of thioamide and N-methyl-thioamide bonds in linear as well as macrocyclic peptide scaffolds in the mRNA-dependent manner, showing its potential for applications in peptide-based drug discovery and studying peptide/protein structure and function.
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