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. 2014 Jul 2;136(26):9244-7.
doi: 10.1021/ja503450q. Epub 2014 Jun 20.

Comparative metabolomics and structural characterizations illuminate colibactin pathway-dependent small molecules

Maria I Vizcaino  1 , Philipp Engel, Eric Trautman, Jason M Crawford
Affiliations

Comparative metabolomics and structural characterizations illuminate colibactin pathway-dependent small molecules

Maria I Vizcaino et al. J Am Chem Soc. .

Abstract

The gene cluster responsible for synthesis of the unknown molecule "colibactin" has been identified in mutualistic and pathogenic Escherichia coli. The pathway endows its producer with a long-term persistence phenotype in the human bowel, a probiotic activity used in the treatment of ulcerative colitis, and a carcinogenic activity under host inflammatory conditions. To date, functional small molecules from this pathway have not been reported. Here we implemented a comparative metabolomics and targeted structural network analyses approach to identify a catalog of small molecules dependent on the colibactin pathway from the meningitis isolate E. coli IHE3034 and the probiotic E. coli Nissle 1917. The structures of 10 pathway-dependent small molecules are proposed based on structural characterizations and network relationships. The network will provide a roadmap for the structural and functional elucidation of a variety of other small molecules encoded by the pathway. From the characterized small molecule set, in vitro bacterial growth inhibitory and mammalian CNS receptor antagonist activities are presented.

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Figures

Figure 1
Figure 1
Venn diagram depicting colibactin pathway-dependent molecular features encoded by the clb locus of E. coli IHE3034 and EcN.
Figure 2
Figure 2
Colibactin pathway-dependent metabolites clustered based on their MS2 fingerprint. Pink nodes (circles) were structurally characterized, and purple nodes indicate ions whose structures are proposed based on HRMS, fragmentation patterns, and network connections. Connectivity strength is represented by the thickness of lines connecting individual nodes.
Figure 3
Figure 3
Biosynthetic proposal for formation of clb metabolites up to the structural complexity represented by 9. Proposed intramolecular cyclization of 10 after being released from 3 by ClbP is also shown. C, condensation; A, adenylation; T, thiolation; E, epimerization; KS, ketosynthase; AT, acyl-transferase; KR, ketoreductase; DH, dehydratase; ER, enoyl-reductase.
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References

    1. Dethlefsen L.; McFall-Ngai M.; Relman D. A. Nature 2007, 449, 811. - PMC - PubMed
    1. Greenblum S.; Turnbaugh P. J.; Borenstein E. Proc. Natl. Acad. Sci. U.S.A. 2011, 109, 594. - PMC - PubMed
    1. Cho I.; Blaser M. J. Nat. Rev. Genet. 2012, 13, 260. - PMC - PubMed
    1. Phelan V. V.; Liu W. T.; Pogliano K.; Dorrestein P. C. Nat. Chem. Biol. 2012, 8, 26. - PMC - PubMed
    1. Rath C. M.; Dorrestein P. C. Curr. Opin. Microbiol. 2012, 15, 147. - PMC - PubMed

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