Reactivity of an Unusual Amidase May Explain Colibactin's DNA Cross-Linking Activity

Yindi Jiang, Alessia Stornetta, Peter W Villalta, Matthew R. Wilson, Paul D. Boudreau, Li Zha, Silvia Balbo, Emily P. Balskus

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Certain commensal and pathogenic bacteria produce colibactin, a small-molecule genotoxin that causes interstrand cross-links in host cell DNA. Although colibactin alkylates DNA, the molecular basis for cross-link formation is unclear. Here, we report that the colibactin biosynthetic enzyme ClbL is an amide bond-forming enzyme that links aminoketone and β-keto thioester substrates in vitro and in vivo. The substrate specificity of ClbL strongly supports a role for this enzyme in terminating the colibactin NRPS-PKS assembly line and incorporating two electrophilic cyclopropane warheads into the final natural product scaffold. This proposed transformation was supported by the detection of a colibactin-derived cross-linked DNA adduct. Overall, this work provides a biosynthetic explanation for colibactin's DNA cross-linking activity and paves the way for further study of its chemical structure and biological roles.

Original languageEnglish (US)
Pages (from-to)11489-11496
Number of pages8
JournalJournal of the American Chemical Society
Volume141
Issue number29
DOIs
StatePublished - Jul 24 2019

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amidase
DNA
Enzymes
Substrates
Amides
Catalyst supports
Scaffolds
Bacteria
Molecules
DNA Adducts
Mutagens
Substrate Specificity
Biological Products
colibactin

PubMed: MeSH publication types

  • Journal Article

Cite this

Jiang, Y., Stornetta, A., Villalta, P. W., Wilson, M. R., Boudreau, P. D., Zha, L., ... Balskus, E. P. (2019). Reactivity of an Unusual Amidase May Explain Colibactin's DNA Cross-Linking Activity. Journal of the American Chemical Society, 141(29), 11489-11496. https://doi.org/10.1021/jacs.9b02453

Reactivity of an Unusual Amidase May Explain Colibactin's DNA Cross-Linking Activity. / Jiang, Yindi; Stornetta, Alessia; Villalta, Peter W; Wilson, Matthew R.; Boudreau, Paul D.; Zha, Li; Balbo, Silvia; Balskus, Emily P.

In: Journal of the American Chemical Society, Vol. 141, No. 29, 24.07.2019, p. 11489-11496.

Research output: Contribution to journalArticle

Jiang, Yindi ; Stornetta, Alessia ; Villalta, Peter W ; Wilson, Matthew R. ; Boudreau, Paul D. ; Zha, Li ; Balbo, Silvia ; Balskus, Emily P. / Reactivity of an Unusual Amidase May Explain Colibactin's DNA Cross-Linking Activity. In: Journal of the American Chemical Society. 2019 ; Vol. 141, No. 29. pp. 11489-11496.
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