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Divergent biosynthesis yields a cytotoxic aminomalonate-containing precolibactin

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.

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Figure 1: Structures and biosynthesis of precolibactins.
Figure 2: Effect of ClbQ on the production of different precolibactins.

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 

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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.

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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.

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The authors declare no competing financial interests.

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Supplementary Text and Figures

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

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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

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