Quadruplet codons allow multiplexing of non-canonical amino acids within single polypeptides in living cells. We show that including high-usage triplet codons after quadruplet codons can improve their decoding efficiency in genetic circuits, which allowed us to develop a system for the programmable biosynthesis of exotic macrocyclic peptides in cells.
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Change history
07 October 2024
Following a correction to the article which this research briefing is based on (Costello, A. et al. Efficient genetic code expansion without host genome modifications. Nat. Biotechnol. https://doi.org/10.1038/s41587-024-02385-y (2024)), Fig. 1 has been updated to amend the top left chemical structure.
References
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Dunkelmann, D. L., Oehm, S. B., Beattie, A. T. & Chin, J. W. A 68-codon genetic code to incorporate four distinct non-canonical amino acids enabled by automated orthogonal mRNA design. Nat. Chem. 13, 1110–1117 (2021). This paper describes quadruplet decoding with orthogonal ribosomes.
DeBenedictis, E. A., Carver, G. D., Chung, C. Z., Soll, D. & Badran, A. H. Multiplex suppression of four quadruplet codons via tRNA directed evolution. Nat. Commun. 12, 5706 (2021). This paper describes our previous efforts to decode quadruplet codons with E. coli tRNAs.
Costello, A. & Badran, A. H. Synthetic biological circuits within an orthogonal central dogma. Trends Biotechnol. 39, 59–71 (2021). This perspective article highlights the importance of orthogonality in genetic circuits aiming to expand the central dogma.
Townend, J. E. & Tavassoli, A. Traceless production of cyclic peptide libraries in E. coli. ACS Chem. Biol. 11, 1624–1630 (2016). This paper developed the split-intein system for circular ligation of peptides and proteins we adapted for peptide macrocyclization.
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This is a summary of: Costello, A. et al. Efficient genetic code expansion without host genome modifications. Nat. Biotechnol. https://doi.org/10.1038/s41587-024-02385-y (2024).
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Recoded gene circuits for multiplexed genetic code expansion. Nat Biotechnol (2024). https://doi.org/10.1038/s41587-024-02387-w
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DOI: https://doi.org/10.1038/s41587-024-02387-w
