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 GPR84GPR84The Xenorhabdus nematophila LrhA transcriptional regulator modulates production of γ-keto-N-acyl amides with inhibitory activity against mutualistic host nematode egg hatching
Lam Y, Hamchand R, Mucci N, Kauffman S, Dudkina N, Reagle E, Casanova-Torres Á, DeCuyper J, Chen H, Song D, Thomas M, Palm N, Goodrich-Blair H, Crawford J. The Xenorhabdus nematophila LrhA transcriptional regulator modulates production of γ-keto-N-acyl amides with inhibitory activity against mutualistic host nematode egg hatching. Applied And Environmental Microbiology 2024, 90: e00528-24. PMID: 38916293, PMCID: PMC11267870, DOI: 10.1128/aem.00528-24.Peer-Reviewed Original ResearchRegulatory hierarchyG protein-coupled receptorsSmall molecule signalsHost-bacteria interactionsSymbiotic relationshipNatural productsHuman G protein-coupled receptorsAmino acid metabolismRegulating amino acid metabolismNull mutantsDiverse natural productsSecondary metabolismNematode progeny productionPathogen interactionsGlobal regulatorNematode egg hatchingWild typeInsect hostsSecondary metabolitesHatching rateLrhAAcylated appendagesMolecular networksMolecule signalsAmide signals
2023
Gut microbes modulate (p)ppGpp during a time-restricted feeding regimen
Ontai-Brenning A, Hamchand R, Crawford J, Goodman A. Gut microbes modulate (p)ppGpp during a time-restricted feeding regimen. MBio 2023, 14: e01907-23. PMID: 37971266, PMCID: PMC10746209, DOI: 10.1128/mbio.01907-23.Peer-Reviewed Original ResearchIdentification of Efflux Substrates Using a Riboswitch-Based Reporter in Pseudomonas aeruginosa
Urdaneta-Páez V, Hamchand R, Anthony K, Crawford J, Sutherland A, Kazmierczak B. Identification of Efflux Substrates Using a Riboswitch-Based Reporter in Pseudomonas aeruginosa. MSphere 2023, 8: e00069-23. PMID: 36946743, PMCID: PMC10117056, DOI: 10.1128/msphere.00069-23.Peer-Reviewed Original ResearchConceptsLiquid chromatography-mass spectrometryCompound uptakeHigh-resolution liquid chromatography-mass spectrometryChromatography-mass spectrometryNovel antibioticsHigh-throughput screeningRational designMore rational designChemical librariesDiverse compoundsInitial hitsSelect compoundsPermeable compoundsDrug candidatesCompoundsStructural propertiesBacterial cellsPowerful methodAntifolate drugsSubstrateSpectrometrySynthesisPseudomonas aeruginosaClasses of antibioticsMembrane
2022
Cellular Stress-Induced Metabolites in Escherichia coli
Gatsios A, Kim C, York A, Flavell R, Crawford J. Cellular Stress-Induced Metabolites in Escherichia coli. Journal Of Natural Products 2022, 85: 2626-2640. PMID: 36346625, PMCID: PMC9949963, DOI: 10.1021/acs.jnatprod.2c00706.Peer-Reviewed Original ResearchCommensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites
Cao Y, Oh J, Xue M, Huh WJ, Wang J, Gonzalez-Hernandez JA, Rice TA, Martin AL, Song D, Crawford JM, Herzon SB, Palm NW. Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites. Science 2022, 378: eabm3233. PMID: 36302024, PMCID: PMC9993714, DOI: 10.1126/science.abm3233.Peer-Reviewed Original ResearchConceptsColorectal cancerInflammatory bowel disease patientsBowel disease patientsInflammatory bowel diseaseIndigenous gut microbesBowel diseaseDisease patientsCommensal microbiotaDNA damageColon tumorigenesisElicit DNA damageGut microbesGenotoxic metabolitesGut commensalsMorganella morganiiPatientsGenotoxic chemicalsDiseaseMicrobiotaMetabolitesGenotoxicityCancerMiceFull spectrumDamageN‐Acyl Amides from Neisseria meningitidis and Their Role in Sphingosine Receptor Signaling
Cho W, York AG, Wang R, Wyche TP, Piizzi G, Flavell RA, Crawford JM. N‐Acyl Amides from Neisseria meningitidis and Their Role in Sphingosine Receptor Signaling. ChemBioChem 2022, 23: e202200490-e202200490. PMID: 36112057, PMCID: PMC9762135, DOI: 10.1002/cbic.202200490.Peer-Reviewed Original ResearchConceptsN-acyl amidesGram-negative opportunistic pathogenNeisseria meningitidisHuman-associated bacteriaBlood-brain barrierBioactive small moleculesInterleukin-10 signalingMacrophage cell typesN-acyltransferaseInterleukin-17AG proteinsHuman diseasesT cellsReceptor signalingCell typesImmune systemHigh mortalityHuman microbiotaRepresentative membersOpportunistic pathogenMeningitidisSignalingSmall moleculesN.MeningitisLACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages
Wei Z, Oh J, Flavell RA, Crawford JM. LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages. Nature 2022, 609: 348-353. PMID: 35978195, PMCID: PMC9813773, DOI: 10.1038/s41586-022-05111-3.Peer-Reviewed Original ResearchConceptsInflammatory bowel diseaseWild-type activityCentral regulatory roleMammalian immune systemBone marrow-derived macrophagesInflammatory macrophagesBiochemical functionsBowel diseaseSignaling outcomesMarrow-derived macrophagesPattern recognition receptorsInflammatory diseasesBiochemical roleRegulatory roleMechanistic connectionUnidentified pathwaySalmonella enterica TyphimuriumNitric oxide synthaseRecognition receptorsHost damageHuman inflammatory diseasesMultiple inflammatory diseasesEnterica TyphimuriumOrnithine decarboxylaseLACC1RNA m6A demethylase ALKBH5 regulates the development of γδ T cells
Ding C, Xu H, Yu Z, Roulis M, Qu R, Zhou J, Oh J, Crawford J, Gao Y, Jackson R, Sefik E, Li S, Wei Z, Skadow M, Yin Z, Ouyang X, Wang L, Zou Q, Su B, Hu W, Flavell RA, Li HB. RNA m6A demethylase ALKBH5 regulates the development of γδ T cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2203318119. PMID: 35939687, PMCID: PMC9388086, DOI: 10.1073/pnas.2203318119.Peer-Reviewed Original ResearchConceptsDemethylase ALKBH5Messenger RNAΓδ T cellsΓδ T cell biologyCommon posttranscriptional modificationΓδ T cell developmentT cell biologyT cell developmentCell precursorsT cell precursorsMammalian cellsRNA modificationsPosttranscriptional modificationsTissue homeostasisCell biologyT cellsTarget genesCheckpoint roleCell developmentM6A demethylase ALKBH5ALKBH5Γδ T-cell originΓδ T cell repertoireCell populationsEarly developmentFossil biomolecules reveal an avian metabolism in the ancestral dinosaur
Wiemann J, Menéndez I, Crawford JM, Fabbri M, Gauthier JA, Hull PM, Norell MA, Briggs DEG. Fossil biomolecules reveal an avian metabolism in the ancestral dinosaur. Nature 2022, 606: 522-526. PMID: 35614213, DOI: 10.1038/s41586-022-04770-6.Peer-Reviewed Original ResearchConceptsHigh metabolic rateCretaceous mass extinctionTerminal Cretaceous mass extinctionLate Cretaceous taxaMetabolic rateCrown mammalsAvian lineagesAncestral stateEcological nichesGiant sauropodsCretaceous taxaMammalsMetabolic abilitiesMetabolic performanceMass extinctionBirdsPhysiological activityEndothermyAvian metabolismCostly adaptationsMetabolismVivo accumulationTheropodsOrnithischiansEctothermsCross-kingdom expression of synthetic genetic elements promotes discovery of metabolites in the human microbiome
Patel JR, Oh J, Wang S, Crawford JM, Isaacs FJ. Cross-kingdom expression of synthetic genetic elements promotes discovery of metabolites in the human microbiome. Cell 2022, 185: 1487-1505.e14. PMID: 35366417, PMCID: PMC10619838, DOI: 10.1016/j.cell.2022.03.008.Peer-Reviewed Original ResearchConceptsSynthetic genetic elementsGenetic elementsBiosynthetic gene clusterCross-species expressionCross-species interactionsDiverse organismsGene clusterBiosynthetic machineryHeterologous expressionRegulatory regionsTRNA synthetasesBiosynthetic pathwayNative contextTranslational activityBiosynthetic capacityHuman microbiomeMetabolic capacityPositive bacteriaSmall moleculesExpressionPathwayValuable compoundsLactobacillus inersEukaryotesSynthetases
2021
A Conserved Nonribosomal Peptide Synthetase in Xenorhabdus bovienii Produces Citrulline-Functionalized Lipopeptides
Li JH, Cho W, Hamchand R, Oh J, Crawford JM. A Conserved Nonribosomal Peptide Synthetase in Xenorhabdus bovienii Produces Citrulline-Functionalized Lipopeptides. Journal Of Natural Products 2021, 84: 2692-2699. PMID: 34581573, PMCID: PMC9970011, DOI: 10.1021/acs.jnatprod.1c00573.Peer-Reviewed Original ResearchConceptsNonribosomal peptide synthetasePeptide synthetaseBiosynthetic gene clusterComparative genomic analysisFree-living infective juvenilesNRPS genesEffector proteinsInsect larvaeSpecialized metabolitesGene clusterMutualistic relationshipXenorhabdus bovieniiHeterologous expressionGenomic analysisRichest producersEntomopathogenic bacteriumSecondary metabolitesHost larvaeInfective juvenilesTermination domainInhibitor pathwayExogenous alcoholsLarvaeSpeciesComplex arrayEscherichia coli small molecule metabolism at the host–microorganism interface
Gatsios A, Kim CS, Crawford JM. Escherichia coli small molecule metabolism at the host–microorganism interface. Nature Chemical Biology 2021, 17: 1016-1026. PMID: 34552219, PMCID: PMC8675634, DOI: 10.1038/s41589-021-00807-5.Peer-Reviewed Original ResearchConceptsSmall molecule metabolismE. coliHost-bacteria interfaceModel organismsHost-bacterial interactionsChemical arsenalMolecule metabolismEscherichia coliHuman microbiotaColiSmall molecule chemistryMetabolismCommon componentSignalingOrganismsBiologyDisease modulationCommensalEscherichiaHostPathogenic roleRoleMicrobiotaMembersNatural Products: An Era of Discovery in Organic Chemistry
Crawford JM, Tang GL, Herzon SB. Natural Products: An Era of Discovery in Organic Chemistry. The Journal Of Organic Chemistry 2021, 86: 10943-10945. PMID: 34412479, DOI: 10.1021/acs.joc.1c01753.Peer-Reviewed Original ResearchEscherichia coli-Derived γ‑Lactams and Structurally Related Metabolites Are Produced at the Intersection of Colibactin and Fatty Acid Biosynthesis
Kim CS, Turocy T, Moon G, Shine EE, Crawford JM. Escherichia coli-Derived γ‑Lactams and Structurally Related Metabolites Are Produced at the Intersection of Colibactin and Fatty Acid Biosynthesis. Organic Letters 2021, 23: 6895-6899. PMID: 34406772, PMCID: PMC10577019, DOI: 10.1021/acs.orglett.1c02461.Peer-Reviewed Original ResearchConceptsFatty acid biosynthesisAcid biosynthesisHybrid polyketide-nonribosomal peptideNuclear magnetic resonance spectroscopyΓ-lactam derivativesUnknown biological activityBiosynthetic logicMagnetic resonance spectroscopyCancer initiationColorectal cancer initiationStereochemical analysisΓ-lactamsColibactinResonance spectroscopyDiverse collectionBiosynthesisBiological activityAbundant metabolitesPathwayRelated metabolitesRelated structuresMetabolitesLociProteinSpectroscopyMolecules from the Microbiome
Shine EE, Crawford JM. Molecules from the Microbiome. Annual Review Of Biochemistry 2021, 90: 1-27. PMID: 33770448, DOI: 10.1146/annurev-biochem-080320-115307.Peer-Reviewed Original ResearchConceptsHuman microbiomeSpecific microbial moleculesSmall moleculesSecond genomeEcological nichesSpecies compositionGenetic capacityInteraction networksMicrobial moleculesMicrobiome editingBiochemical complexitySynthetic biologyMolecular mechanismsHuman cellsImmune system developmentChemical biologyFunctional interactionMicrobiomeDetailed mechanistic studiesBiologyHost responseMechanistic studiesGenomeMoleculesMicrobesA community resource for paired genomic and metabolomic data mining
Schorn MA, Verhoeven S, Ridder L, Huber F, Acharya DD, Aksenov AA, Aleti G, Moghaddam JA, Aron AT, Aziz S, Bauermeister A, Bauman KD, Baunach M, Beemelmanns C, Beman JM, Berlanga-Clavero MV, Blacutt AA, Bode HB, Boullie A, Brejnrod A, Bugni TS, Calteau A, Cao L, Carrión VJ, Castelo-Branco R, Chanana S, Chase AB, Chevrette MG, Costa-Lotufo LV, Crawford JM, Currie CR, Cuypers B, Dang T, de Rond T, Demko AM, Dittmann E, Du C, Drozd C, Dujardin JC, Dutton RJ, Edlund A, Fewer DP, Garg N, Gauglitz JM, Gentry EC, Gerwick L, Glukhov E, Gross H, Gugger M, Guillén Matus DG, Helfrich EJN, Hempel BF, Hur JS, Iorio M, Jensen PR, Kang KB, Kaysser L, Kelleher NL, Kim CS, Kim KH, Koester I, König GM, Leao T, Lee SR, Lee YY, Li X, Little JC, Maloney KN, Männle D, Martin H. C, McAvoy AC, Metcalf WW, Mohimani H, Molina-Santiago C, Moore BS, Mullowney MW, Muskat M, Nothias LF, O’Neill E, Parkinson EI, Petras D, Piel J, Pierce EC, Pires K, Reher R, Romero D, Roper MC, Rust M, Saad H, Saenz C, Sanchez LM, Sørensen SJ, Sosio M, Süssmuth RD, Sweeney D, Tahlan K, Thomson RJ, Tobias NJ, Trindade-Silva AE, van Wezel GP, Wang M, Weldon KC, Zhang F, Ziemert N, Duncan KR, Crüsemann M, Rogers S, Dorrestein PC, Medema MH, van der Hooft JJJ. A community resource for paired genomic and metabolomic data mining. Nature Chemical Biology 2021, 17: 363-368. PMID: 33589842, PMCID: PMC7987574, DOI: 10.1038/s41589-020-00724-z.Peer-Reviewed Original Research
2020
Dual Targeting of v-ATPase and mTORC1 Signaling Disarms Multidrug-Resistant Cancers
Turocy T, Crawford JM. Dual Targeting of v-ATPase and mTORC1 Signaling Disarms Multidrug-Resistant Cancers. Cell Chemical Biology 2020, 27: 1329-1331. PMID: 33217311, DOI: 10.1016/j.chembiol.2020.10.013.Peer-Reviewed Original ResearchMaking and Breaking Leupeptin Protease Inhibitors in Pathogenic Gammaproteobacteria
Li J, Oh J, Kienesberger S, Kim NY, Clarke DJ, Zechner EL, Crawford J. Making and Breaking Leupeptin Protease Inhibitors in Pathogenic Gammaproteobacteria. Angewandte Chemie International Edition 2020, 59: 17872-17880. PMID: 32609431, DOI: 10.1002/anie.202005506.Peer-Reviewed Original ResearchConceptsBacterial small moleculesTripeptide aldehyde protease inhibitorsHeterologous expression analysisProtease inhibitorsColonization phenotypesPhotorhabdus speciesHypothetical proteinsNematode hostsPathogenic GammaproteobacteriaExpression analysisBacterial productionAccessory enzymesGenetic distributionProteolytic degradationSmall moleculesEnzymeLeupeptinKlebsiella oxytocaInhibitorsGammaproteobacteriaLigasesXenorhabdusPhotorhabdusBiosynthesisSpeciesMaking and Breaking Leupeptin Protease Inhibitors in Pathogenic Gammaproteobacteria
Li J, Oh J, Kienesberger S, Kim N, Clarke D, Zechner E, Crawford J. Making and Breaking Leupeptin Protease Inhibitors in Pathogenic Gammaproteobacteria. Angewandte Chemie 2020, 132: 18028-18036. DOI: 10.1002/ange.202005506.Peer-Reviewed Original ResearchBacterial small moleculesTripeptide aldehyde protease inhibitorsHeterologous expression analysisProtease inhibitorsPhotorhabdus speciesColonization phenotypesHypothetical proteinsNematode hostsPathogenic GammaproteobacteriaExpression analysisBacterial productionAccessory enzymesGenetic distributionProteolytic degradationSmall moleculesEnzymeLeupeptinKlebsiella oxytocaInhibitorsLigasesXenorhabdusGammaproteobacteriaPhotorhabdusBiosynthesisSpecies