Journal Article

Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage

Li, Zhong-Rui, Zhang, Wei-Peng, Li, Jie, Lai, Jennifer Y. H., Moore, Bradley S., McKinnie, Shaun M. K., Cai, Wenlong, Qian, Pei-Yuan, Zhang, Wenjun

2019

Overview

Colibactin is an assumed human gut bacterial genotoxin, whose biosynthesis is linked to the clb genomic island that has a widespread distribution in pathogenic and commensal human enterobacteria. Colibactin-producing gut microbes promote colon tumour formation and enhance the progression of colorectal cancer via cellular senescence and death induced by DNA double-strand breaks (DSBs); however, the chemical basis that contributes to the pathogenesis at the molecular level has not been fully characterized. Here, we report the discovery of colibactin-645, a macrocyclic colibactin metabolite that recapitulates the previously assumed genotoxicity and cytotoxicity. Colibactin-645 shows strong DNA DSB activity in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism. We also delineate a complete biosynthetic model for colibactin-645, which highlights a unique fate of the aminomalonate-building monomer in forming the C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety through the activities of both the polyketide synthase ClbO and the amidase ClbL. This work thus provides a molecular basis for colibactin’s DNA DSB activity and facilitates further mechanistic study of colibactin-related colorectal cancer incidence and prevention. Colibactin is produced by human enterobacteria and assumed to be a gut bacterial genotoxin. Now, colibactin-645 has been identified as a macrocyclic colibactin metabolite that contains a C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety and induces DNA double-strand breaks in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/326/41 / 631/67/1504 / 631/92/349 / Amidase / Analytical Chemistry / Biochemistry / Biosynthesis / Cancer / Chemistry / Chemistry and Materials Science / Chemistry/Food Science / Colon / Colorectal cancer / Colorectal carcinoma / Copper / Copper - chemistry / Copper - pharmacology / Cytotoxicity / Deoxyribonucleic acid / DNA / DNA Breaks, Double-Stranded - drug effects / DNA damage / Double-strand break repair / Genomic islands / Genotoxicity / Inorganic Chemistry / Intestinal microflora / Macrocyclic Compounds - chemistry / Macrocyclic Compounds - pharmacology / Metabolites / Molecular Conformation / Organic Chemistry / Oxidative Stress - drug effects / Pathogenesis / Peptides - chemistry / Peptides - pharmacology / Physical Chemistry / Polyketide synthase / Polyketides - chemistry / Polyketides - pharmacology / Senescence / Toxicity / Tumors / Yeast