Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

Diverse backbone-cyclized peptides via codon reprogramming

Nature Chemical Biology volume 5, pages 888–890 (2009)Cite this article

Abstract

We report a methodology for the ribosomal synthesis of backbone-cyclized peptides involving genetic code reprogramming to introduce one or more nonproteinogenic amino acids. Expression of linear peptides bearing a cysteine-proline dipeptide sequence followed by glycolic acid results in self-rearrangement to a C-terminal diketopiperadine-thioester, which non-enzymatically generates a cyclized peptide. We demonstrate the ribosomal synthesis of several naturally occurring backbone-cyclized peptides and a library based on a bicyclic scaffold, and we identify bioactive sequences by screening and deconvolution.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Ribosomal expression of backbone-cyclic peptides.
Figure 2: One-pot expression of RTD-1, its N-methylated analog RTDMe, and SFTI-1.

Similar content being viewed by others

References

  1. Trabi, M. & Craik, D.J. Trends Biochem. Sci. 27, 132–138 (2002).

    Article  CAS  Google Scholar 

  2. Kohli, R.M. & Walsh, C.T. Chem. Commun. (Camb.) 297–307 (2003).

  3. Tang, Y.Q. et al. Science 286, 498–502 (1999).

    Article  CAS  Google Scholar 

  4. Ladner, R.C. Trends Biotechnol. 13, 426–430 (1995).

    Article  CAS  Google Scholar 

  5. Kawakami, T. & Aimoto, S. Chem. Lett. 36, 76–77 (2007).

    Article  CAS  Google Scholar 

  6. Ohta, A., Murakami, H., Higashimura, E. & Suga, H. Chem. Biol. 14, 1315–1322 (2007).

    Article  CAS  Google Scholar 

  7. Shimizu, Y. et al. Nat. Biotechnol. 19, 751–755 (2001).

    Article  CAS  Google Scholar 

  8. Murakami, H., Ohta, A., Ashigai, H. & Suga, H. Nat. Methods 3, 357–359 (2006).

    Article  CAS  Google Scholar 

  9. Ohuchi, M., Murakami, H. & Suga, H. Curr. Opin. Chem. Biol. 11, 537–542 (2007).

    Article  CAS  Google Scholar 

  10. Goto, Y. et al. ACS Chem. Biol. 3, 120–129 (2008).

    Article  CAS  Google Scholar 

  11. Donia, M.S. et al. Nat. Chem. Biol. 2, 729–735 (2006).

    Article  CAS  Google Scholar 

  12. Whyte, A.C., Joshi, B.K., Gloer, J.B., Wicklow, D.T. & Dowd, P.F. J. Nat. Prod. 63, 1006–1009 (2000).

    Article  CAS  Google Scholar 

  13. Kawakami, T., Murakami, H. & Suga, H. Chem. Biol. 15, 32–42 (2008).

    Article  CAS  Google Scholar 

  14. Selsted, M.E. Curr. Protein Pept. Sci. 5, 365–371 (2004).

    Article  CAS  Google Scholar 

  15. Kimura, R.H., Tran, A.T. & Camarero, J.A. Angew. Chem. Int. Edn Engl. 45, 973–976 (2006).

    Article  CAS  Google Scholar 

  16. Wang, W. et al. J. Biol. Chem. 281, 32755–32764 (2006).

    Article  CAS  Google Scholar 

  17. Korsinczky, M.L., Schirra, H.J. & Craik, D.J. Curr. Protein Pept. Sci. 5, 351–364 (2004).

    Article  CAS  Google Scholar 

  18. King, R.W., Lustig, K.D., Stukenberg, P.T., McGarry, T.J. & Kirschner, M.W. Science 277, 973–974 (1997).

    Article  CAS  Google Scholar 

  19. Rungpragayphan, S., Nakano, H. & Yamane, T. FEBS Lett. 540, 147–150 (2003).

    Article  CAS  Google Scholar 

  20. Roberts, R.W. & Szostak, J.W. Proc. Natl. Acad. Sci. USA 94, 12297–12302 (1997).

    Article  CAS  Google Scholar 

  21. Ueno, S., Arai, H., Suzuki, M. & Husimi, Y. Int. J. Biol. Sci. 3, 365–374 (2007).

    Article  CAS  Google Scholar 

  22. Forster, A.C. et al. Proc. Natl. Acad. Sci. USA 100, 6353–6357 (2003).

    Article  CAS  Google Scholar 

  23. Kawakami, T., Murakami, H. & Suga, H. J. Am. Chem. Soc. 130, 16861–16863 (2008).

    Article  CAS  Google Scholar 

  24. Ohta, A., Yamagishi, Y. & Suga, H. Curr. Opin. Chem. Biol. 12, 159–167 (2008).

    Article  CAS  Google Scholar 

  25. Scott, C.P., Abel-Santos, E., Wall, M., Wahnon, D.C. & Benkovic, S.J. Proc. Natl. Acad. Sci. USA 96, 13638–13643 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (16101007) and a research and development project of the Japanese Industrial Science and Technology Program in the New Energy and Industrial Technology Development Organization (NEDO) to H.S. T.K. and A.O. are supported by JSPS Research Fellowships for young scientists (20-664 and 19-1722, respectively).

Author information

Author notes

  1. Takashi Kawakami and Atsushi Ohta: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan

    Takashi Kawakami, Atsushi Ohta, Hiroshi Ashigai & Hiroaki Suga

  2. Department of Advanced Interdisciplinary Studies, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan

    Masaki Ohuchi & Hiroaki Suga

  3. Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

    Hiroshi Murakami & Hiroaki Suga

Authors
  1. Takashi Kawakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Atsushi Ohta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masaki Ohuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroshi Ashigai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroshi Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroaki Suga
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.K., A.O. and H.S. designed the project. T.K., A.O., M.O., H.A. and H.M. performed experiments. The manuscript was written by T.K., A.O. and H.S.

Corresponding author

Correspondence to Hiroaki Suga.

Supplementary information

Supplementary Text and Figures

Supplementary Methods and Supplementary Results (PDF 861 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kawakami, T., Ohta, A., Ohuchi, M. et al. Diverse backbone-cyclized peptides via codon reprogramming. Nat Chem Biol 5, 888–890 (2009). https://doi.org/10.1038/nchembio.259

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.259

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing