Thioesters Support Efficient Protein Biosynthesis by the Ribosome

Kent, Alexandra D. [University of California, Berkeley, CA (United States)]; Robins, Jacob G. [Yale Univ., New Haven, CT (United States)]; Knudson, Isaac J. [University of California, Berkeley, CA (United States)]; Vance, Jessica T. [University of California, Berkeley, CA (United States)] (ORCID:0009000263009646); Solivan, Alexander C. [University of California, Berkeley, CA (United States)]; Hamlish, Noah X. [University of California, Berkeley, CA (United States)]; Fitzgerald, Katelyn A. [University of California, Berkeley, CA (United States)]; Schepartz, Alanna [University of California, Berkeley, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)] (ORCID:0000000321273932); Miller, Scott J. [Yale Univ., New Haven, CT (United States)] (ORCID:0000000178171318); Cate, Jamie D. [University of California, Berkeley, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)] (ORCID:0000000159657902)

doi:10.1021/acscentsci.4c01698

DOE OSTI · 2565626

Thioesters Support Efficient Protein Biosynthesis by the Ribosome

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Abstract

Thioesters are critical chemical intermediates in numerous extant biochemical reactions and are invoked as key reagents during prebiotic peptide synthesis on an evolving Earth. Here we asked if a thioester could replace the native oxo-ester in acyl-tRNA substrates during protein biosynthesis by the ribosome. We prepared 3'-thio-3'-deoxyadenosine triphosphate in 10 steps from xylose and demonstrated that it is an effective substrate for the Escherichia coli CCA-adding enzyme, which appends 3'-thio-3'-deoxyadenosine to truncated tRNAs ending with 3'-CC. Using a variety of aminoacyl-tRNA synthetases, flexizymes, or a direct thioester exchange reaction, we prepared a suite of 3'-thio-tRNAs acylated with α- and non-α-amino acids. All were recognized and utilized by wild-type E. coli ribosomes during in vitro translation reactions to generate oligopeptides in yields commensurate with native oxo-ester tRNAs. These results indicate that thioester intermediates widely used in Nature can be co-opted to support the incorporation of natural α-amino acids as well as noncanonical monomers by the extant translational machinery for sequence-defined polymer synthesis.

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY 59 BASIC BIOLOGICAL SCIENCES genetics monomers organic compounds organic reactions peptides and proteins

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Kent, Alexandra D. [University of California, Berkeley, CA (United States)], Robins, Jacob G. [Yale Univ., New Haven, CT (United States)], Knudson, Isaac J. [University of California, Berkeley, CA (United States)], Vance, Jessica T. [University of California, Berkeley, CA (United States)] (ORCID:0009000263009646), Solivan, Alexander C. [University of California, Berkeley, CA (United States)], Hamlish, Noah X. [University of California, Berkeley, CA (United States)], Fitzgerald, Katelyn A. [University of California, Berkeley, CA (United States)], Schepartz, Alanna [University of California, Berkeley, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)] (ORCID:0000000321273932), Miller, Scott J. [Yale Univ., New Haven, CT (United States)] (ORCID:0000000178171318), Cate, Jamie D. [University of California, Berkeley, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)] (ORCID:0000000159657902). 2025-01-30. Thioesters Support Efficient Protein Biosynthesis by the Ribosome. https://doi.org/10.1021/acscentsci.4c01698

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