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 journalArticlepeer-review

37 Scopus citations


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
Issue number29
StatePublished - Jul 24 2019

Bibliographical note

Publisher Copyright:
© 2019 American Chemical Society.


Dive into the research topics of 'Reactivity of an Unusual Amidase May Explain Colibactin's DNA Cross-Linking Activity'. Together they form a unique fingerprint.

Cite this