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.

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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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Supplementary Notes 1–3. (PDF 6943 kb)

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Li, Z., Li, J., Gu, J. 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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