Ribosome-mediated biosynthesis of pyridazinone oligomers in vitro

Joongoo Lee*, Jaime N. Coronado, Namjin Cho, Jongdoo Lim, Brandon M. Hosford, Sangwon Seo, Do Soon Kim, Camila Kofman, Jeffrey S. Moore, Andrew D. Ellington, Eric V. Anslyn*, Michael C. Jewett*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

The ribosome is a macromolecular machine that catalyzes the sequence-defined polymerization of L-α-amino acids into polypeptides. The catalysis of peptide bond formation between amino acid substrates is based on entropy trapping, wherein the adjacency of transfer RNA (tRNA)-coupled acyl bonds in the P-site and the α-amino groups in the A-site aligns the substrates for coupling. The plasticity of this catalytic mechanism has been observed in both remnants of the evolution of the genetic code and modern efforts to reprogram the genetic code (e.g., ribosomal incorporation of non-canonical amino acids, ribosomal ester formation). However, the limits of ribosome-mediated polymerization are underexplored. Here, rather than peptide bonds, we demonstrate ribosome-mediated polymerization of pyridazinone bonds via a cyclocondensation reaction between activated γ-keto and α-hydrazino ester monomers. In addition, we demonstrate the ribosome-catalyzed synthesis of peptide-hybrid oligomers composed of multiple sequence-defined alternating pyridazinone linkages. Our results highlight the plasticity of the ribosome’s ancient bond-formation mechanism, expand the range of non-canonical polymeric backbones that can be synthesized by the ribosome, and open the door to new applications in synthetic biology.

Original languageEnglish (US)
Article number6322
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

Funding

Research reported in this publication was supported by the Army Research Office (W911NF-16-1-0372) and the National Institute of General Medical Sciences of the National Institutes of Health (F31GM140662 to J.N.C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Army Research Office or the National Institutes of Health. This work was supported in part by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2021R1C1C1006129 to J.L.) and the Welch Regents Chair to E.V.A. (F-0046).

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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