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Selenium and the Thioredoxin and Glutaredoxin Systems

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Selenium and the Thioredoxin and Glutaredoxin Systemsand,the,The

    Selenium and the Thioredoxin and

    Glutaredoxin Systems

BIOMEDICALANDENVIRONMENTAlSCIENCES10,271279(1997)

    ;SeleniumandtheThibredOxinand

    ;GIutaredOxinSystems

    ;MIKAELBJORNSTEDT.SUSHILKUMAR,LINDABJORKHEM,

    ;GIANNISSPYROU,ANDARNEHOLMGREN

    ;TheMedicalNobelInstituteforBiochemistry,Departmentof ;MedicalBiochemistryandBiophysics,Karolinska

    ;Institute,S-17I77Stockholm,Sweden;

    ;*DepartmentofBioscience,Karolinska

    ;Institute,Norum,S14157

    ;Huddinge,Sweden

    ;Thioredoxin(Trx)isasmallubiquitousdithiolproteinwhichtogetherwiththeFA).

    ;containingenzymethioredoxinreductase(TR)andNADPH(theTrxsystem)isahydrogen

    ;donorforribonucleotidereductaseessentialforDNAsynthesisandageneralproteindisulfide

    ;reductaseinvolvedinredoxregulation.Selenite,selenodiglutathione(GSSe-

SG)andseleno

    ;cystineareefficientlyreducedbythioredoxinsandalsodirectlybyNADPHandmammalJan

    SGwiththe;TRbutnotbytheE.colienzyme.IncubationofseleniteorGS-Se

    Trxsystem

    ;orwithmammalianTRresultsinarapidformationofselenide,whichbyredoxcyclingwith

    ;oxygenmaycausealargenon.stoichiometricoxidationofNADPH.Selenocystineisefficiently

    ;reducedintotwomoleculesoftheselenolaminoaeidselenocysteinebymarllmalianTRwitha

    ;Km-value(6t~mol?L-1)andahighturnovernumber(kI3200min-1)almostidenticalto

    ;thenaturalsubstrateTrx-&.TRalsodirectlyreduceslipidhydroperoxidesandthisperoxidase

    ;reactionisstronglystimulatedbythepresenceofcatalyticamountsoffreeselenocysteine.

    ;Glutaredoxin(Grx)whichcatalyzesGSH.dependentdisulfidereductionalsoviaaredoxactive

    ;disulfideandT

    arebothefficientelectrondonorstothehumanplasmaglutathioneperoxi. ;dazeprovidingamechanismbywhichhumanplasmaglutathioneperoxidase

mayreducehy.

    ;dropemxidesinanenvironmentalmostfreefromglutathione.SelenateisreducedbyGrxand

    ;TrxinthepresenceofGSH.TheDNA.bindingofthetranscriptionfactorAP.1isstronglyin.

    ;hibitedbyGsSe-SGandselenite.Furthermore,selenideformedbvTR.mediatedreductionof

    ;seleniteandGS-SeSGinhibitslipoxygenaseandchangestheelectronspinresonancespectrum

    ;oftheactivesiteiton.MammalianTRwithtwosubunitsof57kDahasrecentlybeencloned

    ;andshowntobehomologoustoglutathionereductase.Theratenzymecontaimsaselenocys.

    ;teineresidueinauniqueCterminalpositionandaconservedSECISsequencedirectinginsertion

    ;oftheselenocysteine.ThediscoveryofselenocysteineinmammalianTRmayexplainthe

    ;broadsubstratespecificityoftheenzymeandtherequirementofseleniumforcellproliferation.

    ;THETHIOREDoXINSYSTEM

    ;Thioredoxin(Trx)isa12kDaproteinwitharedoxactivedisulfideandhasbeen ;Theabbreviationsusedinthispaperare:Enz-Se

,selenolate;Enz.SeOH,selenenicacid;GR,

    ;glutathionereduc

    ;tase;Grx,glutaredoxin;GSH,reducedglutathione;GSSG,oxidizedglutathione;GS-Se.SG.selenodiglu.

    ;tathione;I-IPETE,hydmpemxy-eicosatetmenoicacid;

    ;Trx,thioredoxin;TrxS2,oxidizedTrx;Trx.(SH)2;

    ;ROH,alcohol;ROOH,hydropemxide;Se.selenide

    ;reducedTrx;TR,thioredoxinreductase.

    ;271

    ;0895.3988/97

    ;CN11.2816

    ;Copyright?1997byCAPM

    ;

    ;272BJORNSTEDTETAL

    ;purifiedandcharacterizedfromawidevarietyofprokaryoticandeukaryoticspecies

    ;(Holmgren,1985;1989).TrxandtheFADcontainingenzymethioredoxinr

    educ

    ;tase(TR)togetherwithNADPH(theTrxsystem)isageneralproteindisulfidere

    ;ductaseandahydrogendonorforribonucleotidereductaseessentialforDNAsynthesis

    ;(Holmgren,1985;1989;HolmgrenandBj6rnstedt,1995).ASageneralprotein

    ;disulfidereductase,Trxcanregulatetheactivityofenzymesandtranscriptionfactors

    ;bythiolredoxcontro1.Themechanisminvolvesthereversibleformationofadisulfide

    ;involvingthesulfurofacriticalcysteineSH.groupandanotherSH.groupeitherwith

    ;inaproteinortoglutathione(GSH).Trxiswidelydistributedinmammaliantissues

    ;andcellsandthecalculatedcellularconcentratione.g.inliverisaround10/~mol?L

    ;(HolmgrenandLuthman,1978;Grankvisteta1.,1982;Rozelleta1.,1985).Trx

    ;isalsopresentincalfserum(HolmgrenandLuthman,1978)andhumanplasma

    ;(Nakamuraeta1.,1996)inaconcentrationtwotothreeordersofmagnitudelower

    ;comparedtocellsandissecretedbynormalandneoplasticcellsthroughaleaderless

    ;secretorypathway(Ericsoneta1.,1992;Rubertellieta1.,1992).Trxsecreted ;fromactivatedhumanlymphocytesupregulatesIL

2receptors.synergizeswithIL1

    ;andIL.2andhasbeensuggestedtobeanimportantmodulatoroftheimmunesystem

    ;andintheregulationofcellgrowth(Tagayaeta1.,1989;Wakasugieta1.,1990; ;YodoiandTursz,1991;Ros~neta1.,1995).

    ;THEGLUTAREDOXINSYSTEM

    ;Glutaredoxin(Grx)isa10kDaproteinoriginallydiscoveredasaGSH.depen. ;denthydrogendonortoribonucleotidereductaseinanE.colimutantlakcingTrx

    ;(Holmgren,1976).Theproteincontainsaredox.activedisulfide/dithiolintheactive

    ;siteandcatalyzesgeneralGSHdisulfideoxidoreductions(Holmgren,1989;Holm.

    ;grenandAslund,1995).ReductionofGrxisachievedbvGSHandtheGSSGformed

    ;inthisreactionisreducedbyglutathionereductaseandNADPH.Grxhasbeenpuri.

    ;fledfromseveralmammaliansourcesincludinginourlaboratorycalfthymus(Luth

    ;manandHolmgren,1982)andhumanplacenta(Padillaeta1.,1995)andwasre. ;centlyidentifiedinhumanplasmainrelativelyhighconcentrationscomparedtoTrx

    ;(Nakamuraeta1.,1997).Constantglutaredoxinandelevatedthioredoxinlevelsin

    ;humanplasmaduringcardiacsurgerywithcardiopulmonarybypass(submitted).Re.

    ;cently,twoadditionalglutaredoxins(Grx.2andGrx.3)wereidentifiedinanE.coli

    ;mutantlackingbothTrxandtheclassicalGrx(Grx

    1)(Aslundeta1.,1994),indi.

    ;caringthatacomplexpatternofisoenzymesispresentincells. ;REDUCT10N0FSELENITEANDGSe.SG

    ;SeleniteandGS-Se.SGarereducedbyeitherthemammalianandE.coliTrx ;systemsoralsodirectlybymammalianTRintheabsenceofTrx(Bi6rnstedteta1..

    ;1992;Kumareta1.,1992;Bj6rnstedteta1.,1995b).Additionofseleniteatlow ;concentrations(110/~mol?LI1)tomammalianTRresultsinanonstoichiometricox

    ;idationofNADPHinthepresenceofoxygen(Kumareta1.,1992;Bi6rnstedtPt ;

    Z.,1995b)afteraninitiallagphase.Anaerobicallythereactionstopsaftertheoxida

    ;tionof3molesofNADPHpermolofselenite,con.sistentwiththeforlTlationofse

;lenide(HSe/Sez):

    ;5r:t?fl毒?J.{‘I??Il;}}

    ;

    ;SELENIUM,THIOREDOXINANDGLUTAREDOXINSYSTEMS273

    ;SeO2+3NADPH+3HSe+3H2O+3NADP

    ;AdditionofGSSeSGtomammalianTRresultsinafastinitialoxidationofa ;stoichiometricamountofNADPH,consistentwithcleavageofthemolecule,followed

    ;byaslowernonstoichiometriccontinousreaction.Anaerobicallythereactionstopsal

    ;terthefomationofselenide.Theaerobicnonstoichiometricparto?theabov

    ereac

    ;tionsisexplainedbytheregenerationofselenidewhichhasbeenoxidizedby02.

    ;REDUCTIONOFSELENOCYSTINEANDSELENATE

    ;Selenocystine,adiselenideaminoacid.isreducedbyhumanTRintotwo ;rnoleculesoftheselenolaminoacidselenocysteine.TheKmforselenocystineis6rnol

    ;?

    ;L1andthe

    3200minI1(Table1)comparedtoflKmof2’9mol?L_.andflkt

    ;of2800minI1fortheclassicalsubstrateTrx(Reneta1.,1993).Thekineticpa

    ;rametersthusclearlyshowthatthediselenideaminoacidselenocystineisalmostan

    ;equallygoodsubtrateasthenaturalsubstrateTrxtohumanTR.Selenohomocystine

    ;wasalsoefficientlyreducedbyhumanTR(Table1.).Onthecontrarythesulfur ;analogcystinewasnotreducedbyhumanTR.Theresultsindicatethatexposeddisc?

    ;lenidebridgesarekeptreducedintheceUbyTR.

    ;TABLE1

    ;KineticParametersfortheReductionofDiselenidesbyHumanThioredoxinReductas&

    ;Bi6rnstedteta1.,’(1997).manuscriptinpreparation

    ;Inselenateseleniumexistsinitshighest.oxidationstate(+V1).Sincethissele

    ;niumcompoundhasflverylowreactivitywiththiolscomparedtoselenite,the ;metabolismofselenatetomakeitbioavailablehasbeenlargelyunknown.Wehavere

    ;centlydiscoveredthatselenatewasreducedbyhumanGrxandtheTrxsysteminthe

    ;presenceofreducedGSH(Bj6rnstedt,M.eta1.(1997).Selenateisreducedby ;glutaredoxinsthroughamixed.disulfidemechanismandbythethioredoxinsystemin

    ;thepresenceofGSH(submitted).SelenatewasnotreducedbytheTrxsystemin

    ;theabsenceofGSH.TheresultssuggestthatanintermediateisformedbetweenGSH

    ;andselenate.Thisintermediatecannotbefurtherreducedbyanothermoleculeof

    ;GSHtomoreredox.activeformslikeselenite.However.thepresenceoftheTrxsys

    ;ternorGrxwithhighlyreactivenucleophilicthiolateslcadstofurtherreduction.

    ;Thus,bytheTrxandGrxsystemsselenateismadeaccessibletoanorganism.Con

    ;trarytoselenatetheanalogousoxyanionssulfateandarsenatewerenotreducedbythe

    ;TrxsystemorGrxinthepresenceofGSH.

    ;REDUCTIONOFHYDR0PER0XIDES

    ;Humanplasmaglutathioneperoxidaseisaselenoenzyme,whichhasbeenas

    ;sum.edtouseGSHasanelectrondonor.However,sincethelevelofGSHinplasmais

    ;

    ;274BJ0RNSTEDTETAL

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