2024
Human AKR1C3 binds agonists of GPR84 and participates in an expanded polyamine pathway
Dudkina N, Park H, Song D, Jain A, Khan S, Flavell R, Johnson C, Palm N, Crawford J. Human AKR1C3 binds agonists of GPR84 and participates in an expanded polyamine pathway. Cell Chemical Biology 2024 PMID: 39163853, DOI: 10.1016/j.chembiol.2024.07.011.Peer-Reviewed Original ResearchHuman aldo-keto reductase family 1 member C3Mammalian fatty acid synthaseDNA double-strand break responseDouble-strand break responseAldo-keto reductase family 1 member C3Associated with poor prognosisPolyamine pathwayFatty acid synthesisFatty acid synthaseAcid synthaseAKR1C3 activityPoor prognosisBiochemical roleAcid synthesisClinical significanceLigand screeningFerroptosis resistanceDNA damageAKR1C3Metabolic diseasesDiverse cancersDNANADPHAgonists of GPR84GPR84
2020
Structure and bioactivity of colibactin
Wernke KM, Xue M, Tirla A, Kim CS, Crawford JM, Herzon SB. Structure and bioactivity of colibactin. Bioorganic & Medicinal Chemistry Letters 2020, 30: 127280. PMID: 32527463, PMCID: PMC7309967, DOI: 10.1016/j.bmcl.2020.127280.Peer-Reviewed Original ResearchConceptsColibactin-producing bacteriaStrands of DNABiosynthetic pathwaySecondary metabolitesColibactinMolecular-level explanationHuman gutAdenine residuesCell contactElectrophilic CyclopropanesCertain strainsBacteriaGenotoxic effectsHeterodimersDNABacterial cultureResiduesPathwayCleavageCellsStrandsGut
2019
Structure elucidation of colibactin and its DNA cross-links
Xue M, Kim CS, Healy AR, Wernke KM, Wang Z, Frischling MC, Shine EE, Wang W, Herzon SB, Crawford JM. Structure elucidation of colibactin and its DNA cross-links. Science 2019, 365 PMID: 31395743, PMCID: PMC6820679, DOI: 10.1126/science.aax2685.Peer-Reviewed Original ResearchConceptsColibactin-producing bacteriaCell biology dataColibactin gene clusterCombination of geneticsComplex secondary metabolitesGene clusterIsotope labelingSecondary metabolitesBiology dataColibactinHuman gutTandem mass spectrometryBacteriaPhysiological effectsMass spectrometryStructure elucidationGutGeneticsDNAEnzymeChemical synthesisEscherichiaElucidationMetabolitesLabeling
2018
Characterization of Natural Colibactin–Nucleobase Adducts by Tandem Mass Spectrometry and Isotopic Labeling. Support for DNA Alkylation by Cyclopropane Ring Opening
Xue M, Shine E, Wang W, Crawford JM, Herzon SB. Characterization of Natural Colibactin–Nucleobase Adducts by Tandem Mass Spectrometry and Isotopic Labeling. Support for DNA Alkylation by Cyclopropane Ring Opening. Biochemistry 2018, 57: 6391-6394. PMID: 30365310, PMCID: PMC6997931, DOI: 10.1021/acs.biochem.8b01023.Peer-Reviewed Original ResearchConceptsGenotoxic secondary metabolitesMethionine auxotrophic strainsE. coliGut commensal Escherichia coliClb gene clusterColibactin biosynthesisElectrophilic CyclopropanesGene clusterDNA alkylationPrevious biosynthetic studiesSecondary metabolitesAuxotrophic strainsEscherichia coliCommensal Escherichia coliBiosynthetic studiesFirst identificationBiosynthesisColiColibactinPUC19 DNAIsotopic labelingNucleotidesDNATandem mass spectrometryCertain strains
2016
A Mechanistic Model for Colibactin-Induced Genotoxicity
Healy AR, Nikolayevskiy H, Patel JR, Crawford JM, Herzon SB. A Mechanistic Model for Colibactin-Induced Genotoxicity. Journal Of The American Chemical Society 2016, 138: 15563-15570. PMID: 27934011, PMCID: PMC5359767, DOI: 10.1021/jacs.6b10354.Peer-Reviewed Original ResearchConceptsGene clusterE. coliDNA double-strand breaksDouble-strand breaksProbiotic Nissle 1917Clb gene clusterEukaryotic cellsCertain commensalDNA bindingProbiotic E. coliDisparate phenotypesPrecolibactinsAlkylate DNAColibactinIsolation effortsFermentation productsColiDNA alkylationDNANissle 1917Mechanistic modelSide chainsNatural productsMetabolite structuresEfficient DNA alkylation
2015
The colibactin warhead crosslinks DNA
Vizcaino MI, Crawford JM. The colibactin warhead crosslinks DNA. Nature Chemistry 2015, 7: 411-417. PMID: 25901819, PMCID: PMC4499846, DOI: 10.1038/nchem.2221.Peer-Reviewed Original ResearchConceptsDNA-damaging activityHost-microbe interactionsUncharacterized familyColibactin biosynthesisSmall moleculesHybrid pathwayCancer formationMode of actionDuplex DNACrosslinks DNAMicrobial metabolitesUnexpected modelHuman microbiotaSelect strainsMetabolomic analysisDNAPathwayEscherichia coli presentHuman colonLabeling studiesDisease statesDirect experimental evidenceHuman healthBiosynthesisColibactin