Chapter23 TCA cycle.ppt

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1、Chapter23TCACycle,OverviewofTCAcycleAllTCAcyclereactionsSummaryoftheTCAcyclePhysiologicalfunctionsoftheTCAcycleTheGlyoxylateCycleAnapleroticreactionsoftheTCAcycleRegulationoftheTCAcycle,Outline,OverviewofTCAcycle,akaCitricAcidCycle,KrebsCycleAcommonmetabolicpathwayforglucose,aaandfattyacidPyruvate(a

2、ctuallyacetate)fromglycolysisisdegradedtoCO2SomeATPisproducedMoreNADHismadeNADHgoesontomakemoreATPinelectrontransportandoxidativephosphorylation,AllroadsleadtoTCAcylce,EntryintotheTCACycle,PyruvateDehydrogenase(PDH)ComplexPyruvateisoxidativelydecarboxylatedtoformacetyl-CoAPyruvatedehydrogenaseusesTP

3、P,CoASH,lipoicacid,FADandNAD+Pyruvatedehydrogenase(E1)Dihydrolipoamidetransacetylase(E2)Dihydrolipoamidedehydrogenase(E3),lipoicacidanditslinkagewithE2,PyruvateDehydrogenaseComplexofE.coli,ThefivereactionsofthePDHmultienzymecomplex,ArsenicCompoundsArePoisonousinpartbecausetheySequesterLipoamide,AllT

4、CAcyclereactions,Formationofcitrate,CatalyzedbyCitrateSynthaseAnotherexamplefortheinducedfitmodelOAA,thefirstsubstratetobindtotheenzyme,inducealargeconformationalchange,creatingabindingsiteforthesecondsubstrate,acetyl-CoA.Whencitroyl-CoAformsontheenzymesurface,anotherconformationalchangebringsthesid

5、eofacrucialAspresidueintopositiontocleavagethethioester.Thismechanismdecreasesthelikelihoodofprematureandunproductivecleavageofthethioesterbondofacetyl-CoA,FormationofCitrateandFluorocitrate,Conformationalchangesincitratesynthase,TheOpenConformation,Theclosed,substrate-bindingconformation,Isomerizat

6、ionofCitratetoIsocitrate,CatalyzedbyAconitaseCitrateisapoorsubstrateforoxidationSoaconitaseisomerizescitratetoyieldisocitratewhichhasasecondary-OH,whichcanbeoxidizedNotethestereochemistryoftheRxn:aconitaseremovesthepro-RHofthepro-Rarmofcitrate!Aconitaseusesaniron-sulfurcluster,IsomerizationofCitrate

7、toIsocitrate,Amechanismforaconitasereaction,StereochemistryoftheAconitaseReaction,OxidativeDecarboxylationofIsocitrate,CatalyzedbyIsocitrateDehydrogenase(IDH)ClassicNAD+chemistry(hydrideremoval)followedbyadecarboxylationIsocitratedehydrogenaseisalinktotheelectrontransportpathwaybecauseitmakesNADHKno

8、wthemechanism!,ThereactionmechanismofIDH,Asecondoxidativedecarboxylation,Catalyzedby-KetoglutarateDehydrogenaseComplexThisenzymeisnearlyidenticaltopyruvatedehydrogenase-structurallyandmechanisticallyFivecoenzymesused-TPP,CoASH,Lipoicacid,NAD+,FADYouknowthemechanismifyourememberpyruvatedehydrogenaseA

9、nothertargetforarseniccompounds,OxidativeDecarboxylationof-Ketoglutarate,Asubstrate-levelphosphorylation,CatalyzedbySuccinyl-CoASynthetaseAnucleosidetriphosphateismadeItssynthesisisdrivenbyhydrolysisofaCoAesterThemechanisminvolvesaphosphohistidine,Thesubstrate-levelphosphorylation,Thereactionmechani

10、smofsuccinyl-CoAsynthetase,AnoxidationinvolvingFAD,CatalyzedbySuccinateDehydrogenaseThisenzymeisactuallypartoftheelectrontransportpathway(ComplexII)intheinnermitochondrialmembraneTheelectronstransferredfromsuccinatetoFAD(toformFADH2)arepasseddirectlytoubiquinone(UQ)intheelectrontransportpathway,Dehy

11、drogenationofSuccinate,Hydrationacrossthedoublebond,CatalyzedbyFumarasetrans-additionoftheelementsofwateracrossthedoublebondTheactualmechanismisnotknownforcertain,Hydrationacrossthedoublebond,AnNAD+-dependentoxidation,CatalyzedbyMalateDehydrogenaseThecarbonthatgetsoxidizedistheonethatreceivedthe-OHi

12、nthepreviousreactionThisreactionisenergeticallyexpensive,Go=+30kJ/molThisandtheprevioustworeactionsformareactiontriadthatwewillseeoverandover!,RegenerationofOAA,TheFateofCarboninTCA,CarboxylCofacetateturnstoCO2onlyinthesecondturnofthecycle(followingentryofacetate)MethylCofacetatesurvivestwocyclescom

13、pletely,buthalfofwhatsleftexitsthecycleoneachturnafterthat.,Totalrxn:Acetyl-CoA+3NAD+FAD+GDP+Pi+2H2O2CO2+3NADH+FADH2+GTP+2H+CoAOneAcetyl-CoAthroughthecycleproducestwoCO2,oneATP,fourreducedcoenzymesTwoH2OsareusedassubstratesAbsolutelydependsonO2,FunctionoftheTCACycle,ProducesMoreATPsAsasourceofbiosyn

14、theticprecursorsAcommonfinalmetabolicpathwayforglucose,aasandfattyacidsSomeImmediatesactaseffectorstoregulateothermetabolicpathwaysProducesCO2,StoichiometryofCoenzymeReductionandATPFormationDuringtheCompleteOxidationofGlucose,Amphibolicfunctionsofthecitricacidcycle,AnapleroticReactions,TheGlyoxylate

15、Cycle,AvariantofTCAforplantsandbacteriaAcetate-basedgrowth-netsynthesisofcarbohydratesandotherintermediatesfromacetate-isnotpossiblewithTCAGlyoxylatecycleoffersasolutionforplantsandsomebacteriaandalgaeTheCO2-evolvingstepsarebypassedandanextraacetateisutilizedIsocitratelyaseandmalatesynthasearethesho

16、rt-circuitingenzymes,GlyoxylateCycleII,IsocitratelyaseproducesglyoxylateandsuccinateMalatesynthasedoesaClaisencondensationofacetyl-CoAandthealdehydegroupofglyoxylate-classicCoAchemistry!Theglyoxylatecyclehelpsplantsgrowinthedark!Glyoxysomesborrowthreereactionsfrommitochondria:succinatetooxaloacetate,TheGlyoxylateCycle,Electronmicrographagerminatingcucumberseed,showingaglyoxysomemitochondriaandsurroundinglipidbodies,RelationshipbetweentheglyoxylateandTCAcycles,CoordinatedregulationofglyoxylateandTCAcycles,RegulationoftheTCAcycle,