Escherichia coli-Derived γ‑Lactams and Structurally Related Metabolites Are Produced at the Intersection of Colibactin and Fatty Acid Biosynthesis

• Published in: Organic letters Vol. 23; no. 17; pp. 6895 - 6899
• Main Authors: Kim, Chung Sub, Turocy, Tayah, Moon, Gyuri, Shine, Emilee E, Crawford, Jason M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 03-09-2021
• Subjects: DNA Damage; Escherichia coli - chemistry; Escherichia coli - metabolism; Escherichia coli Proteins - genetics; Fatty Acids - chemistry; Fatty Acids - metabolism; Humans; Lactams - chemistry; Lactams - metabolism; Molecular Structure; Peptides - chemistry; Polyketides - chemistry
• ISSN: 1523-7060; 1523-7052
• DOI: 10.1021/acs.orglett.1c02461

Colibactin is a genotoxic hybrid polyketide-nonribosomal peptide that drives colorectal cancer initiation. While clinical data suggest colibactin genotoxicity in vivo is largely caused by the major DNA-cross-linking metabolite, the colibactin locus produces a diverse collection of metabolites with mostly unknown biological activities. Here, we describe 10 new colibactin pathway metabolites (1–10) that are dependent on its α-aminomalonyl-carrier protein. The most abundant metabolites, 1 and 2, were isolated and structurally characterized mainly by nuclear magnetic resonance spectroscopy to be γ-lactam derivatives, and the remaining related structures were inferred via shared biosynthetic logic. Our proposed formation of 1–10, which is supported by stereochemical analysis, invokes cross-talk between colibactin and fatty acid biosynthesis, illuminating further the complexity of this diversity-oriented pathway.