OMIMOnlineMendelianInheritanceinManAll DatabasesPubMedNucleotideProteinGenomeStructurePMCTaxonomyOMIM SearchPubMedProteinNucleotideCoreNucleotideGSSESTStructureGenomeBooksCancerChromosomesConservedDomainsdbGaP3DDomainsGeneGenomeProjectGENSATGEOProfilesGEODataSetsHomoloGeneJournalsMeSHNCBIWebSiteNLMCatalogOMIAOMIMPMCPopSetProbeProteinClustersPubChemBioAssayPubChemCompoundPubChemSubstanceSNPTaxonomyToolKitUniGeneUniSTSLimitsPreview/IndexHistoryClipboardDetailsDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardAll1OMIMdbSNP0OMIMUniSTS0*100880LinksACONITASESOLUBLEACO1AlternativetitlessymbolsIRONRESPONSIVEELEMENTBINDINGPROTEIN1IREB1IREBINDINGPROTEIN1IRP1IREBPGenemaplocus9p22p13TEXTSlaughteretal(1975)reportedthatanelectrophoreticsurveyhaddemonstrated7allelesatthislocusAmongthepopulationsstudiedNigeriansshowedpolymorphismforACONSAconitasecatalyzestheconversionofcisaconitatetoisocitrateInstudiesofmanChinesehamstersomaticcellhybridsWesterveldetal(1975)showedthathumangal1puridyltransferase(GALT606999)andaconitasearesyntenicPoveyetal(1976)assignedtheACO1genetochromosome9ACO1andGALTareon9pinmanandonchromosome4inthemouse(NadeauandEicher1982)ThelocationinthemousewaspredictedfromthehumanlinkageThesmallestregionofoverlap(SRO)forACO1wasestimatedtobe9p22p13(RobsonandMeeraKhan1982)Aconitase1andaconitase2(ACO2100850)areisozymespresentinthecytosolandmitochondriarespectivelyOtherpairsofcytosolicandmitochondrialisozymesareALDH1(100640)andALDH2(100650)GOT1(138180)andGOT2(138150)IDH1(147700)andIDH2(147650)MDH1(154200)andMDH2(154100)SOD1(147450)andSOD2(147460)andTK1(188300)andTK2(188250)Inallthesecasesthe2isozymesofdifferentsubcellularlocalizationalthoughsimilarinstructureandfunctionareencodedbygenesondifferentchromosomesiearenonsyntenicThepresumptionisthatineachcasebothoriginatedfromacommonancestralgeneinaprimordialgenomebutthatwhereasthecytosolicisozymeisencodedbyagenethatisadirectdescendantfromanuclearprogenitorgenethemitochondrialisozymealthoughnowencodedbyanucleargeneisdescendedfromageneinthebacteriumlikeprogenitorofthemitochondrionWhenthisprimitiveorganismtookupintracellularexistencemostofitsgenesweretransferredtothenucleargenomeandsincetheyinsertedmoreorlessatrandomintothenucleargenomeitwastobeexpectedthatthecytosolicandmitochondrialformsoftheenzymewouldendupbeingencodedbygenesondifferentchromosomesThatmitochondrialDNAcanbeinsertedintothenucleargenomeisindicatedbyworksuchasthatofShayandWerbin(1992)whocharacterizedindetail2instancesofmitochondrialDNAfragmentsthathadbeeninsertedintothenucleusofHeLacellsInoneofthesecasesthemitochondrialsequenceencodingcytochromecoxidasesubunitIIIwascontiguouswithand5primeofexons2and3oftheMYConcogene(190080)andthechimericgenewastranscribedShayandWerbin(1992)discussedpossiblemechanismsforthetransferofmitochondrialDNAintothenucleusDataongenefrequenciesofallelicvariantsweretabulatedbyRoychoudhuryandNei(1988)Aconitase1isanironresponsiveelement(IRE)IREsaretranslationalregulatorysequencesinthe5primeuntranslatedregions(UTRs)offerritinmRNAandinthe3primeUTRsoftransferrinreceptormRNA(190010)ThecytoplasmicIREbindingproteininteractswiththeironresponsiveelementsofmRNATheironstatusofthecelldeterminestheabilityoftheIREBPtobindtoanIREthroughreversibleoxidationreductionofsulfhydrylgroupsthatarecriticalforthehighaffinityRNA/proteininteractionThustheIREBPplaysacentralroleincellularironhomeostasisbyregulatingferritinmRNAtranslationandTFRCmRNAstabilityBecauseofthepossibilitythatidiopathichemochromatosiswhichistheresultofamutantgenethatmapsto6p21isduetomutationinIREBPHentzeetal(1989)attemptedtomapthegenecodingforthebindingproteinSincethegenehadnotbeenclonedandsincetheydidnothavespecificantibodiesfortheproteintheymappedthegeneinhuman/rodenthybridcellsbytakingadvantageofthedifferentmobilitiesofthehumanandrodentIRE/IREBPcomplexesonnondenaturingpolyacrylamidegelsUsingapanelof34differenthybridcelllinestheyassignedtheIREBPgenetohumanchromosome9Rouaultetal(1990)usedRNAaffinitychromatographyand2dimensionalgelelectrophoresistoisolateIREBPforproteinsequencingTheyusedanoligonucleotideprobederivedfromthepeptidesequencetoisolateacDNAthatencodesaproteinof87kDThecorrespondingmRNAofabout36kbwasfoundinavarietyofcelltypesSouthernhybridizationanalysisofrodenthumansomatichybridcelllinescorroboratedtheassignmenttochromosome9AhighfrequencyRFLPwasalsoidentifiedByinterspecificbackcrosslinkageanalysisPilzetal(1995)mappedtheIrebpgenetomousechromosome4Eisenstein(2000)reviewedoftheroleoftheironregulatoryproteinsIRP1andIRP2(147582)andthemolecularcontrolofmammalianironmetabolismIRP1isabifunctionalproteinwithmutuallyexclusivefunctionsasanIRERNAbindingproteinorasthecytoplasmicisoformofaconitaseAconitasesareironsulfurproteinsanda4Fe4SclusterisrequiredfortheirenzymaticactivityMeyronHoltzetal(2004)foundthatIRP2nullcellsmisregulatedironmetabolismwhenculturedin3to6%oxygenwhichiscomparabletophysiologictissueconcentrationsbutnotin21%oxygenaconcentrationthatactivatedIRP1andallowedittosubstituteforIRP2ThusIRP2dominatesregulationofmammalianironhomeostasisbecauseitaloneregistersironconcentrationsandmodulatesitsRNAbindingactivityatphysiologicoxygentensionsBIOCHEMICALFEATURESCrystalStructureIronregulatoryprotein1(IRP1)bindsIREsinmRNAstorepresstranslationordegradationorbindsanironsulfurclustertobecomeacytosolicaconitaseenzymeWaldenetal(2006)determinedthecrystalstructureofIRP1boundtoferritinH(134770)IREto28angstromresolutionTheIRP1ferritinHIREcomplexshowedanopenproteinconformationcomparedwiththatofcytosolicaconitaseTheextendedLshapedIRP1moleculeembracedtheIREstemloopthroughinteractionsat2sitesseparatedbyabout30angstromseachinvolvingaboutadozenproteinRNAbondsWaldenetal(2006)concludedthatextensiveconformationalchangesrelatedtobindingtheIREoranironsulfurclusterexplainthealternatefunctionsofIRP1asanmRNAregulatororenzymeSEEALSOAzevedoetal(1979)Mohandasetal(1979)Robsonetal(1977)ShowsandBrown(1977)Tengetal(1978)REFERENCES1AzevedoESDaSilvaMCBOLimaAMVFonsecaEFConseicaoMMHumanaconitasepolymorphisminthreesamplesfromnortheasternBrazilAnnHumGenet437101979PubMedID4963962EisensteinRSIronregulatoryproteinsandthemolecularcontrolofmammalianironmetabolismAnnuRevNutr206276622000PubMedID109403483HentzeMWSeuanezHNO'BrienSJHarfordJBKlausnerRDChromosomallocalizationofnucleicacidbindingproteinsbyaffinitymappingassignmentoftheIREbindingproteingenetohumanchromosome9NucleicAcidsRes17610361081989PubMedID27716414MeyronHoltzEGGhoshMCRouaultTAMammaliantissueoxygenlevelsmodulateironregulatoryproteinactivitiesinvivoScience306208720902004PubMedID156044065MohandasTSparkesRSSparkesMCShulkinJDToomeyKEFunderburkSJRegionallocalizationofhumangenelocionchromosome9studiesofsomaticcellhybridscontaininghumantranslocationsAmJHumGenet315866001979PubMedID2923066NadeauJHEicherEMConservedlinkageofsolubleaconitaseandgalactose1phosphateuridyltransferaseinmouseandmanassignmentofthesegenestomousechromosome4CytogenetCellGenet342712811982PubMedID62978537PilzAWoodwardKPoveySAbbottCComparativemappingof50humanchromosome9lociinthelaboratorymouseGenomics251391491995PubMedID77749118PoveySSlaughterCAWilsonDEGormleyIPBucktonKEPerryPBobrowMEvidencefortheassignmentofthelociAK1AK3andACONtochromosome9inmanAnnHumGenet394134221976PubMedID1820629RobsonEBCookPJLBucktonKEFamilystudieswiththechromosome9markersABOAK1ACONSand9qhAnnHumGenet4153601977PubMedID20016810RobsonEBMeeraKhanPReportofthecommitteeonthegeneticconstitutionofchromosomes78and9CytogenetCellGenet321441521982PubMedID714035711RouaultTATangCKKaptainSBurgessWHHaileDJSamaniegoFMcBrideOWHarfordJBKlausnerRDCloningofthecDNAencodinganRNAregulatoryproteinthehumanironresponsiveelementbindingproteinProcNatAcadSci87795879621990PubMedID217296812RoychoudhuryAKNeiMHumanPolymorphicGenesWorldDistributionNewYorkOxfordUnivPress(pub)198813ShayJWWerbinHNewevidencefortheinsertionofmitochondrialDNAintothehumangenomesignificanceforcancerandagingMutatRes2752272351992PubMedID138376414ShowsTBBrownJAMappingAK1ACONSandAK3tochromosome9inmanemployinganX9translocationandsomaticcellhybridsCytogenetCellGenet1926371977PubMedID19681315SlaughterCAHopkinsonDAHarrisHAconitasepolymorphisminmanAnnHumGenet391932021975PubMedID105276616TengYSTanSGLopezCGRedcellglyoxalaseIandplacentalsolubleaconitasepolymorphismsinthethreemajorethnicgroupsofMalaysiaJpnJHumGenet23211215197817WaldenWESeleznevaAIDupuyJVolbedaAFontecillaCampsJCTheilECVolzKStructureofdualfunctionironregulatoryprotein1complexedwithferritinIRERNAScience314190319082006PubMedID1718559718WesterveldAvanHenegouwenBHMAVanSomerenHEvidenceforsyntenybetweenthehumanlociforgalactose1phosphateuridyltransferaseandaconitaseinmanChinesehamstersomaticcellhybridsCytogenetCellGenet144534541975PubMedID1192837CONTRIBUTORSAdaHamoshupdated2/6/2007AdaHamoshupdated1/27/2005VictorAMcKusickupdated9/28/2001CREATIONDATEVictorAMcKusick6/4/1986EDITHISTORYalopez2/8/2007terry2/6/2007wwang2/3/2005terry1/27/2005carol6/7/2002carol10/3/2001mcapotos9/28/2001carol7/12/2000mimadm2/11/1994carol2/17/1993carol2/2/1993carol8/25/1992supermim3/16/1992carol12/6/1990Copyright©19662007JohnsHopkinsUniversityDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardDisclaimerWritetotheHelpDeskPrivacyPolicyNCBINLMNIH