A5042300089- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- DNA Repair Mechanisms
- Bacterial Genetics and Biotechnology
- Microbial Natural Products and Biosynthesis
- Cancer therapeutics and mechanisms
- Carcinogens and Genotoxicity Assessment
- Gut microbiota and health
- Pharmacogenetics and Drug Metabolism
- CRISPR and Genetic Engineering
- Microbial Metabolic Engineering and Bioproduction
- Chemical Reactions and Isotopes
- Chemical synthesis and alkaloids
- Catalytic C–H Functionalization Methods
- Cholinesterase and Neurodegenerative Diseases
- Fungal Plant Pathogen Control
- Escherichia coli research studies
- Genomics and Phylogenetic Studies
- Berberine and alkaloids research
- Vitamin C and Antioxidants Research
- Traditional and Medicinal Uses of Annonaceae
- Cancer Research and Treatments
Yale University
2016-2022
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 colorectal cancer in humans. However, because colibactin has not been isolated or structurally characterized, studying physiological effects human difficult. We used combination genetics, isotope labeling, tandem mass spectrometry, chemical synthesis to deduce structure colibactin. Our structural...
Microbiota-derived metabolites that elicit DNA damage can contribute to colorectal cancer (CRC). However, the full spectrum of genotoxic chemicals produced by indigenous gut microbes remains be defined. We established a pipeline systematically evaluate genotoxicity an extensive collection commensals from inflammatory bowel disease patients. identified isolates divergent phylogenies whose caused and discovered distinctive family genotoxins-termed indolimines-produced CRC-associated species...
The lomaiviticins are dimeric genotoxic metabolites that contain unusual diazocyclopentadiene functional groups and 2–4 deoxyglycoside residues. Because only 6 of 19 carbon atoms in the monomeric aglycon unit proton-attached, their structure determination by NMR spectroscopic analysis is difficult. Prior elucidation efforts established two halves joined a single carbon–carbon bond appended to an oxidized cyclohexenone ring. This ring was believed comprise 4,5-dihydroxycyclohex-2-ene-1-one....
Colibactins are genotoxic secondary metabolites whose biosynthesis is encoded in the clb gene cluster harbored by certain strains of gut commensal Escherichia coli. Using synthetic colibactin analogues, we previously provided evidence that colibactins alkylate DNA addition a nucleotide to an electrophilic cyclopropane intermediate. However, natural colibactin-nucleobase adducts have not been identified, best our knowledge. Here present first identification such adducts, derived from...
Colibactin is a genotoxic gut microbiome metabolite long suspected of playing an etiological role in colorectal cancer. Evidence suggests that colibactin forms DNA interstrand cross-links (ICLs) eukaryotic cells and activates ICL repair pathways, leading to the production ICL-dependent double-strand breaks (DSBs). Here we show ICLs can evolve directly DSBs. Using topology supercoiled plasmid as proxy for alkylation adduct stability, find colibactin-derived are unstable toward depurination...
Colibactins are genotoxic secondary metabolites produced in select Enterobacteriaceae, which induce downstream DNA double-strand breaks (DSBs) human cell lines and thought to promote the formation of colorectal tumors. Although key structural functional features colibactins have been elucidated, full molecular mechanisms regulating these phenotypes remain unknown. Here, we demonstrate that free model DSBs cultures do not require delivery by host bacteria. Through domain-targeted editing, a...
(-)-Lomaiviticin A (1) is a C2-symmetric cytotoxin that contains two diazofluorene functional groups and which induces double-strand breaks (DSBs) in DNA. Evidence suggests DNA cleavage initiated by hydrogen atom abstraction from the deoxyribose backbone. Here we demonstrate formation of vinyl radicals 1· 2· 1 1,7-addition thiols to diazofluorenes. These can affect methanol acetone. The first addition thiol proceeds at much greater rate than second. diazosulfide 5 formed en route has been...
Colibactin is a genotoxic metabolite produced by commensal-pathogenic members of the human microbiome that possess clb (aka pks) biosynthetic gene cluster. clb+ bacteria induce tumorigenesis in models intestinal inflammation and have been causally linked to oncogenesis humans. While colibactin believed underlie these effects, it has not possible study molecule directly due its instability. Herein, we report synthesis biological studies 742 (4), stable derivative. We show (4) induces DNA...
Myrocins are a family of antiproliferative antibiotic fungal metabolites possessing masked electrophilic cyclopropane. Preliminary chemical reactivity studies imputed the bioactivity these natural products to DNA cross-linking mechanism, but this hypothesis was not confirmed by with native DNA. We recently reported total synthesis (−)-myrocin G (4), putative active form metabolite myrocin C (1), that featured carefully orchestrated tandem fragment coupling–annulation cascade. Herein, we...
Abstract Colibactin is a gut microbiome metabolite of unknown structure that has been implicated in colorectal cancer formation. Several studies now suggest the tumorgenicity colibactin derives from interstrand cross-linking host DNA. Here we use combination genetics, isotope labeling, tandem MS, and chemical synthesis to deduce colibactin. Our structural assignment accounts for all known biosynthetic data suggests roles final unaccounted enzymes gene cluster. DNA cross-link degradation...
The lomaiviticins are dimeric genotoxic bacterial metabolites that contain unusual diazocyclopentadiene functional groups and 2–4 deoxyglycoside residues. Because only 6 of 19 carbon atoms in the monomeric aglycon unit proton-attached, their structure determination by NMR spectroscopic analysis is non-trivial. Prior elucidation efforts established two halves joined a single carbon–carbon bond appended to an oxidized cyclohexenone ring. This ring was believed comprise...
Abstract Colibactins are genotoxic secondary metabolites produced in select Enterobacteriaceae, which induce downstream DNA double-strand breaks (DSBs) human cell lines and thought to promote the formation of colorectal tumors. Although key structural functional features colibactins have been elucidated, full molecular mechanisms regulating these phenotypes remain unknown. Here, we demonstrate that free model DSBs cultures do not require delivery by host bacteria. Through domain-targeted...
The lomaiviticins are dimeric genotoxic bacterial metabolites that contain unusual diazocyclopentadiene functional groups and 2–4 deoxyglycoside residues. Because only 6 of 19 carbon atoms in the monomeric aglycon unit proton-attached, their structure determination by NMR spectroscopic analysis is non-trivial. Prior elucidation efforts established two halves joined a single carbon–carbon bond appended to an oxidized cyclohexenone ring. This ring was believed comprise...
Abstract Colibactin is a genotoxic gut microbiome metabolite long suspected of playing an etiological role in colorectal cancer progression. Evidence suggests colibactin forms DNA interstrand cross-links (ICLs) eukaryotic cells and activates ICL repair pathways, leading to the production ICL-dependent double-strand breaks (DSBs). Here we show that ICLs can evolve directly DSBs. Using topology supercoiled plasmid as proxy for alkylation adduct stability, colibactin-derived are unstable toward...