| Autor: |
Gatsios A; Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States.; Institute of Biomolecular Design & Discovery, Yale University, West Haven, Connecticut 06516, United States., Kim CS; Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States.; Institute of Biomolecular Design & Discovery, Yale University, West Haven, Connecticut 06516, United States.; School of Pharmacy and Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Republic of Korea., York AG; Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, United States., Flavell RA; Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, United States.; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, United States., Crawford JM; Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States.; Institute of Biomolecular Design & Discovery, Yale University, West Haven, Connecticut 06516, United States.; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06510, United States. |
| Abstrakt: |
Escherichia coli isolates commonly inhabit the human microbiota, yet the majority of E. coli 's small-molecule repertoire remains uncharacterized. We previously employed erythromycin-induced translational stress to facilitate the characterization of autoinducer-3 (AI-3) and structurally related pyrazinones derived from "abortive" tRNA synthetase reactions in pathogenic, commensal, and probiotic E. coli isolates. In this study, we explored the "missing" tryptophan-derived pyrazinone reaction and characterized two other families of metabolites that were similarly upregulated under erythromycin stress. Strikingly, the abortive tryptophanyl-tRNA synthetase reaction leads to a tetracyclic indole alkaloid metabolite ( 1 ) rather than a pyrazinone. Furthermore, erythromycin induced two naphthoquinone-functionalized metabolites (MK-hCys, 2 ; and MK-Cys, 3 ) and four lumazines ( 7 - 10 ). Using genetic and metabolite analyses coupled with biomimetic synthesis, we provide support that the naphthoquinones are derived from 4-dihydroxy-2-naphthoic acid (DHNA), an intermediate in the menaquinone biosynthetic pathway, and the amino acids homocysteine and cysteine. In contrast, the lumazines are dependent on a flavin intermediate and α-ketoacids from the aminotransferases AspC and TyrB. We show that one of the lumazine members ( 9 ), an indole-functionalized analogue, possesses antioxidant properties, modulates the anti-inflammatory fate of isolated T H 17 cells, and serves as an aryl-hydrocarbon receptor (AhR) agonist. These three systems described here serve to illustrate that new metabolic branches could be more commonly derived from well-established primary metabolic pathways. |
