Structure elucidation of colibactin and its DNA cross-links

• Published in: Science (American Association for the Advancement of Science) Vol. 365; no. 6457; p. 1000
• Main Authors: Xue, Mengzhao, Kim, Chung Sub, Healy, Alan R., Wernke, Kevin M., Wang, Zhixun, Frischling, Madeline C., Shine, Emilee E., Wang, Weiwei, Herzon, Seth B., Crawford, Jason M.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 06.09.2019; The American Association for the Advancement of Science
• Subjects: Alkylation; Animal models; Bacteria; Bases (nucleic acids); Biological activity; Biosynthesis; Cancer; Carcinogens; Cell culture; Chemical synthesis; Chemistry; Coliforms; Colorectal cancer; Colorectal carcinoma; Correlation; Crosslinking; Cyclopropane; Cytology; Deoxyribonucleic acid; DNA; DNA Adducts - chemistry; DNA biosynthesis; DNA damage; E coli; Escherichia coli; Escherichia coli - genetics; Escherichia coli - metabolism; Escherichia coli Proteins - genetics; Genetics; Genome editing; Genomes; Genotoxicity; Interdisciplinary Approach; Interdisciplinary aspects; Intermediates; Intestinal microflora; Isotope Labeling; Labeling; Mass spectrometry; Mass spectroscopy; Metabolites; Metabolomics; Microbiomes; Mutation; Natural products; Nucleotides; Organic chemistry; Peptide Hydrolases - genetics; Peptides - chemistry; Peptides - genetics; Peptides - metabolism; Phenotypes; Physiological effects; Physiology; Polyketides - chemistry; Polyketides - metabolism; Precursors; Protein Conformation; RESEARCH ARTICLE SUMMARY; Researchers; Scientific imaging; Secondary Metabolism; Spectroscopy; Strains (organisms); Structure-function relationships; Tandem Mass Spectrometry; Warheads
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aax2685

Strains of the human gut bacterium Escherichia coli carrying the clb gene cluster produce a secondary metabolite dubbed colibactin and have been provocatively linked to colorectal cancer in some models. Colibactin has been difficult to isolate in full, but pieces of the structure have been worked out, including an electrophilic warhead. Xue et al. found that colibactin contains two conjoined warheads, which is consistent with its ability to alkylate and cross-link DNA. Chemical synthesis and comparison to cell coculture confirm the structure and properties of this unstable and potentially carcinogenic metabolite. Science , this issue p. eaax2685 A DNA cross-linking metabolite from gut microbes is made by joining two precursor units. Colibactin is a complex secondary metabolite produced by some genotoxic gut Escherichia coli strains. The presence of colibactin-producing bacteria correlates with the frequency and severity of colorectal cancer in humans. However, because colibactin has not been isolated or structurally characterized, studying the physiological effects of colibactin-producing bacteria in the human gut has been difficult. We used a combination of genetics, isotope labeling, tandem mass spectrometry, and chemical synthesis to deduce the structure of colibactin. Our structural assignment accounts for all known biosynthetic and cell biology data and suggests roles for the final unaccounted enzymes in the colibactin gene cluster.