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:

Divergent biosynthesis yields a cytotoxic aminomalonate-containing precolibactin

Nature Chemical Biology volume 12, pages 773–775 (2016)Cite this article

Subjects

Abstract

Colibactin is an as-yet-uncharacterized genotoxic secondary metabolite produced by human gut bacteria. Here we report the biosynthetic discovery of two new precolibactin molecules from Escherichia coli, including precolibactin-886, which uniquely incorporates the highly sought genotoxicity-associated aminomalonate building block into its unprecedented macrocyclic structure. This work provides new insights into the biosynthetic logic and mode of action of this colorectal-cancer-linked microbial chemical.

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: Structures and biosynthesis of precolibactins.
Figure 2: Effect of ClbQ on the production of different precolibactins.

Similar content being viewed by others

References

  1. Nougayrède, J.P. et al. Science 313, 848–851 (2006).

    Article  Google Scholar 

  2. Bode, H.B. Angew. Chem. Int. Ed. Engl. 54, 10408–10411 (2015).

    Article  CAS  Google Scholar 

  3. Balskus, E.P. Nat. Prod. Rep. 32, 1534–1540 (2015).

    Article  CAS  Google Scholar 

  4. Arthur, J.C. et al. Science 338, 120–123 (2012).

    Article  CAS  Google Scholar 

  5. Welch, R.A. et al. Proc. Natl. Acad. Sci. USA 99, 17020–17024 (2002).

    Article  CAS  Google Scholar 

  6. Olier, M. et al. Gut Microbes 3, 501–509 (2012).

    Article  Google Scholar 

  7. Vizcaino, M.I. & Crawford, J.M. Nat. Chem. 7, 411–417 (2015).

    Article  CAS  Google Scholar 

  8. Li, Z.R. et al. ChemBioChem 16, 1715–1719 (2015).

    Article  CAS  Google Scholar 

  9. Engel, P., Vizcaino, M.I. & Crawford, J.M. Appl. Environ. Microbiol. 81, 1502–1512 (2015).

    Article  Google Scholar 

  10. Brotherton, C.A. & Balskus, E.P. J. Am. Chem. Soc. 135, 3359–3362 (2013).

    Article  CAS  Google Scholar 

  11. Bian, X. et al. ChemBioChem 14, 1194–1197 (2013).

    Article  CAS  Google Scholar 

  12. Brachmann, A.O. et al. Chem. Commun. (Camb.) 51, 13138–13141 (2015).

    Article  CAS  Google Scholar 

  13. Zha, L., Wilson, M.R., Brotherton, C.A. & Balskus, E.P. ACS Chem. Biol. 11, 1287–1295 (2016).

    Article  CAS  Google Scholar 

  14. Vizcaino, M.I., Engel, P., Trautman, E. & Crawford, J.M. J. Am. Chem. Soc. 136, 9244–9247 (2014).

    Article  CAS  Google Scholar 

  15. Brotherton, C.A., Wilson, M., Byrd, G. & Balskus, E.P. Org. Lett. 17, 1545–1548 (2015).

    Article  CAS  Google Scholar 

  16. Bian, X., Plaza, A., Zhang, Y. & Müller, R. Chem. Sci. 6, 3154–3160 (2015).

    Article  CAS  Google Scholar 

  17. Li, Y. et al. Sci. Rep. 5, 9383 (2015).

    Article  CAS  Google Scholar 

  18. Du, L. & Lou, L. Nat. Prod. Rep. 27, 255–278 (2010).

    Article  CAS  Google Scholar 

  19. Patonay, T. & Hoffman, R.V. J. Org. Chem. 60, 2368–2377 (1995).

    Article  CAS  Google Scholar 

  20. Pinho e Melo, T.M.V.D. et al. J. Org. Chem. 67, 66–71 (2002).

    Article  CAS  Google Scholar 

  21. Healy, A.R., Vizcaino, M.I., Crawford, J.M. & Herzon, S.B. J. Am. Chem. Soc. 138, 5426–5432 (2016).

    Article  CAS  Google Scholar 

  22. Aslan, K. et al. Anal. Chem. 80, 4125–4132 (2008).

    Article  CAS  Google Scholar 

  23. Gust, B., Challis, G.L., Fowler, K., Kieser, T. & Chater, K.F. Proc. Natl. Acad. Sci. USA 100, 1541–1546 (2003).

    Article  CAS  Google Scholar 

  24. Kumar, S., Stecher, G. & Tamura, K. Mol. Biol. Evol. 33, 1870–1874 (2016).

    Article  CAS  Google Scholar 

  25. Okonechnikov, K., Golosova, O. & Fursov, M. Bioinformatics 28, 1166–1167 (2012).

    Article  CAS  Google Scholar 

  26. Datsenko, K.A. & Wanner, B.L. Proc. Natl. Acad. Sci. USA 97, 6640–6645 (2000).

    Article  CAS  Google Scholar 

  27. Kouprina, N. & Larionov, V. Nat. Protoc. 3, 371–377 (2008).

    Article  CAS  Google Scholar 

  28. Yamanaka, K. et al. Proc. Natl. Acad. Sci. USA 111, 1957–1962 (2014).

    Article  CAS  Google Scholar 

  29. Liu, T. et al. Chem. Biol. 13, 945–955 (2006).

    Article  CAS  Google Scholar 

  30. Rohm, B., Scherlach, K. & Hertweck, C. Org. Biomol. Chem. 8, 1520–1522 (2010).

    Article  CAS  Google Scholar 

  31. Fujii, K. et al. Anal. Chem. 69, 5146–5151 (1997).

    Article  CAS  Google Scholar 

  32. Ross, A.C. et al. J. Am. Chem. Soc. 135, 1155–1162 (2013).

    Article  CAS  Google Scholar 

  33. Lock, R.B. & Stribinskiene, L. Cancer Res. 56, 4006–4012 (1996).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was generously supported by grants from the China Ocean Mineral Resources Research and Development Association (13.5 program to P.-Y.Q.) and the NIH (R01-GM85770 to B.S.M.). We thank P.R. Jensen, J. Busch, C.B. Naman, and Y.K. Tam for technical advice and access to equipment.

Author information

Author notes

  1. Zhong-Rui Li and Jie Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Life Science and Environmental Science Programs, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.,

    Zhong-Rui Li, Jennifer Y H Lai, Wei-Peng Zhang, Yong-Xin Li & Pei-Yuan Qian

  2. Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, California, USA.,

    Jie Li & Bradley S Moore

  3. High-field NMR Research Center, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China

    Jin-Ping Gu & Dong-Hai Lin

  4. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.,

    Brendan M Duggan & Bradley S Moore

  5. Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.,

    Zhi-Long Li & Rong-Biao Tong

  6. Shenzhen Key Laboratory of Marine Bioresource & Ecoenvironmental Science, Shenzhen Engineering Laboratory for Marine Algal Biotechnology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China

    Ying Xu

Authors
  1. Zhong-Rui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jin-Ping Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jennifer Y H Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Brendan M Duggan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei-Peng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhi-Long Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yong-Xin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rong-Biao Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ying Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Dong-Hai Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Bradley S Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Pei-Yuan Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Z.-R.L., J.L., J.-P.G., J.Y.H.L., B.M.D., W.-P.Z., Z.-L.L., Y.-X.L., R.-B.T., Y.X., and D.-H.L. performed experiments and collected data; all authors analyzed data; Z.-R.L., J.L., B.S.M., and P.-Y.Q. designed the study and wrote the manuscript.

Corresponding authors

Correspondence to Bradley S Moore or Pei-Yuan Qian.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Tables 1–3 and Supplementary Figures 1–18. (PDF 4521 kb)

Supplementary Note

Supplementary Notes 1–3. (PDF 6943 kb)

Source data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, ZR., Li, J., Gu, JP. et al. Divergent biosynthesis yields a cytotoxic aminomalonate-containing precolibactin. Nat Chem Biol 12, 773–775 (2016). https://doi.org/10.1038/nchembio.2157

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.2157

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

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