Synthesis and reactivity of precolibactin 886

Alan Healy, Kevin M. Wernke, Chung Sub Kim, Nicholas R. Lees, Jason M. Crawford, Seth B. Herzon

Research output: Contribution to journalArticle

Abstract

The clb gene cluster encodes the biosynthesis of metabolites known as precolibactins and colibactins. The clb pathway is found in gut commensal Escherichia coli, and clb metabolites are thought to initiate colorectal cancer via DNA crosslinking. Here we report confirmation of the structural assignment of the complex clb product precolibactin 886 via a biomimetic synthetic pathway. We show that an α-ketoimine linear precursor undergoes spontaneous cyclization to precolibactin 886 on HPLC purification. Studies of this α-ketoimine and the related α-dicarbonyl revealed that these compounds are unexpectedly susceptible to nucleophilic cleavage under mildly basic conditions. This cleavage pathway forms other known clb metabolites or biosynthetic intermediates and explains the difficulties in isolating fully mature biosynthetic products. This cleavage also accounts for a recently identified colibactin-adenine adduct. The colibactin peptidase ClbP deacylates synthetic precolibactin 886 to form a non-genotoxic pyridone, which suggests precolibactin 886 lies off the path of the major biosynthetic route.

Original languageEnglish (US)
Pages (from-to)890-898
Number of pages9
JournalNature chemistry
Volume11
Issue number10
DOIs
StatePublished - Oct 1 2019

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Metabolites
Pyridones
Cyclization
Biosynthesis
Biomimetics
Adenine
Crosslinking
Escherichia coli
Purification
DNA
Peptide Hydrolases
Genes
colibactin

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

Healy, A., Wernke, K. M., Kim, C. S., Lees, N. R., Crawford, J. M., & Herzon, S. B. (2019). Synthesis and reactivity of precolibactin 886. Nature chemistry, 11(10), 890-898. https://doi.org/10.1038/s41557-019-0338-2

Synthesis and reactivity of precolibactin 886. / Healy, Alan; Wernke, Kevin M.; Kim, Chung Sub; Lees, Nicholas R.; Crawford, Jason M.; Herzon, Seth B.

In: Nature chemistry, Vol. 11, No. 10, 01.10.2019, p. 890-898.

Research output: Contribution to journalArticle

Healy, A, Wernke, KM, Kim, CS, Lees, NR, Crawford, JM & Herzon, SB 2019, 'Synthesis and reactivity of precolibactin 886', Nature chemistry, vol. 11, no. 10, pp. 890-898. https://doi.org/10.1038/s41557-019-0338-2
Healy A, Wernke KM, Kim CS, Lees NR, Crawford JM, Herzon SB. Synthesis and reactivity of precolibactin 886. Nature chemistry. 2019 Oct 1;11(10):890-898. https://doi.org/10.1038/s41557-019-0338-2
Healy, Alan ; Wernke, Kevin M. ; Kim, Chung Sub ; Lees, Nicholas R. ; Crawford, Jason M. ; Herzon, Seth B. / Synthesis and reactivity of precolibactin 886. In: Nature chemistry. 2019 ; Vol. 11, No. 10. pp. 890-898.
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