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 () and Michael C. Jewett ()
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Joongoo Lee: Northwestern University
Jaime N. Coronado: University of Texas at Austin
Namjin Cho: Pohang University of Science and Technology (POSTECH)
Jongdoo Lim: University of Texas at Austin
Brandon M. Hosford: University of Texas at Austin
Sangwon Seo: Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST)
Do Soon Kim: Northwestern University
Camila Kofman: Northwestern University
Jeffrey S. Moore: University of Illinois at Urbana-Champaign
Andrew D. Ellington: University of Texas at Austin
Eric V. Anslyn: University of Texas at Austin
Michael C. Jewett: Northwestern University

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33701-2

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