Expanding the limits of the second genetic code with ribozymes

Joongoo Lee, Kenneth E. Schwieter, Andrew M. Watkins, Do Soon Kim, Hao Yu, Kevin J. Schwarz, Jongdoo Lim, Jaime Coronado, Michelle Byrom, Eric V. Anslyn, Andrew D. Ellington, Jeffrey S. Moore () and Michael C. Jewett ()
Additional contact information
Joongoo Lee: Northwestern University
Kenneth E. Schwieter: University of Illinois at Urbana−Champaign
Andrew M. Watkins: Stanford University
Do Soon Kim: Northwestern University
Hao Yu: University of Illinois at Urbana−Champaign
Kevin J. Schwarz: University of Illinois at Urbana−Champaign
Jongdoo Lim: University of Texas at Austin
Jaime Coronado: University of Texas at Austin
Michelle Byrom: University of Texas at Austin
Eric V. Anslyn: University of Texas at Austin
Andrew D. Ellington: University of Texas at Austin
Jeffrey S. Moore: University of Illinois at Urbana−Champaign
Michael C. Jewett: Northwestern University

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract The site-specific incorporation of noncanonical monomers into polypeptides through genetic code reprogramming permits synthesis of bio-based products that extend beyond natural limits. To better enable such efforts, flexizymes (transfer RNA (tRNA) synthetase-like ribozymes that recognize synthetic leaving groups) have been used to expand the scope of chemical substrates for ribosome-directed polymerization. The development of design rules for flexizyme-catalyzed acylation should allow scalable and rational expansion of genetic code reprogramming. Here we report the systematic synthesis of 37 substrates based on 4 chemically diverse scaffolds (phenylalanine, benzoic acid, heteroaromatic, and aliphatic monomers) with different electronic and steric factors. Of these substrates, 32 were acylated onto tRNA and incorporated into peptides by in vitro translation. Based on the design rules derived from this expanded alphabet, we successfully predicted the acylation of 6 additional monomers that could uniquely be incorporated into peptides and direct N-terminal incorporation of an aldehyde group for orthogonal bioconjugation reactions.

Date: 2019
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DOI: 10.1038/s41467-019-12916-w

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