A Prodrug Resistance Mechanism Is Involved in Colibactin
Biosynthesis and Cytotoxicity
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Abstract
Commensal Escherichia coli residing
in the human gut produce colibactin, a small-molecule genotoxin of
unknown structure that has been implicated in the development of colon
cancer. Colibactin biosynthesis is hypothesized to involve a prodrug
resistance strategy that entails initiation of biosynthesis via construction
of an N-terminal prodrug scaffold and late-stage cleavage of this
structural motif during product export. Here we describe the biochemical
characterization of the prodrug synthesis, elongation, and cleavage
enzymes from the colibactin biosynthetic pathway. We show that nonribosomal
peptide synthetases ClbN and ClbB assemble and process an <i>N</i>-acyl-d-asparagine prodrug scaffold that serves
as a substrate for the periplasmic d-amino peptidase ClbP.
In addition to affording information about structural features of
colibactin, this work reveals the biosynthetic logic underlying the
prodrug resistance strategy and suggests that cytotoxicity requires
amide bond cleavage