Chapter29 FFA metabolism.ppt

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1、Chapter29FFAmetabolism,Outline,Fattyacidoxidation-oxidation-oxidation-oxidationFormationandutilizationofketonebodiesFattyacidsynthesisRegulationofFFAmetabolism,BetaOxidationofFattyAcids,Knoopshowedthatfattyacidsmustbedegradedbyremovalof2-CunitsAlbertLehningershowedthatthisoccurredinthemitochondriaF.

2、LynenandE.Reichartshowedthatthe2-Cunitreleasedisacetyl-CoA,notfreeacetateTheprocessbeginswithoxidationofthecarbonthatisbetatothecarboxylcarbon,sotheprocessiscalledbeta-oxidation,FranzKnoopsclassicexperimentindicatingthatfattyacidsaremetabolicallyoxidizedattheir-carbonatom,CoAactivatesFAsforoxidation

3、,Acyl-CoAsynthetasecondensesfattyacidswithCoA,withsimultaneoushydrolysisofATPtoAMPandPPiFormationofaCoAesterisexpensiveenergeticallyReactionjustbarelybreaksevenwithATPhydrolysisButsubsequenthydrolysisofPPidrivesthereactionstronglyforwardNotetheacyl-adenylateintermediateinthemechanism!,ConnectingtheF

4、FAtoCoA-SH,CarnitineasaCarrier,CarnitinecarriesfattyacylgroupsacrosstheinnermitochondrialmembraneShortchainfattyacidsarecarrieddirectlyintothemitochondrialmatrixLong-chainfattyacidscannotbedirectlytransportedintothematrixLong-chainFAsareconvertedtoacylcarnitinesandarethentransportedinthecellAcyl-CoA

5、estersareformedinsidetheinnermembraneinthisway,Transportofacyl-carnitineintothematrix,rate-limitingstepforoxidationofFAs,-OxidationofFattyAcids,ARepeatedSequenceof4ReactionsStrategy:createacarbonylgrouponthe-CFirst3reactionsdothat;fourthcleavesthe-ketoesterProducts:anacetyl-CoAandafattyacidtwocarbon

6、sshorter,FADH2,NADHThefirstthreereactionsarecrucialandclassic-wewillseethemagainandagaininotherpathways,oxidation-Fattyacidsaredegradedbyrepeatedcyclesofoxidationattheb-carbonandcleavageoftheC-Cbondtoyieldacetateunits,Oxidationoffattyacids:threesteps,onenew,The-oxidationofsaturatedfattyacids,Acyl-Co

7、ADehydrogenase,OxidationoftheC-CbondAfamilyofthreesolublematrixenzymesMechanisminvolvesprotonabstraction,followedbydoublebondformationandhydrideremovalbyFADElectronsarepassedtoanelectrontransferflavoprotein,andthentotheETCEnzymeisinhibitedbyametaboliteofhypoglycin(fromakeefruit),Theacyl-CoAdehydroge

8、nasereaction,Fourthreaction:thiolase,aka-ketothiolaseCysteinethiolateonenzymeattacksthe-carbonylgroupThiolgroupofanewCoAattackstheshortenedchain,forminganew,shorteracyl-CoAThisisthereverseofaClaisencondensation:attackoftheenolateofacetyl-CoAonathioesterEventhoughitformsanewthioester,thereactionisfav

9、orableanddrivesotherthree,Mechanismofactionofketoacyl-CoAthiolase,Summaryof-Oxidation,RepetitionofthecycleyieldsasuccessionofacetateunitsThus,palmiticacidyieldseightacetyl-CoAsComplete-oxidationofonepalmiticacidyields106moleculesofATPLargeenergyyieldistheconsequenceofthehighlyreducedstateofthecarbon

10、andcompactstorage(nohydration)offattyacids,YieldofATPduringtheCompleteOxidationofOneMoleculeofPalmitoyl-CoA,b-oxidationchallenges,monounsaturatedFA,polyunsaturatedFA,odd-carbonFA,(-CcontainingCH3group),Verylongchainfattyacid(VLCFA),suchas26:0or24:0,UnsaturatedFattyAcids,Considermonounsaturatedfattya

11、cids:Oleicacid,palmitoleicacidNormal-oxidationforthreecyclescis-3acyl-CoAcannotbeutilizedbyacyl-CoAdehydrogenaseEnoyl-CoAisomeraseconvertsthistotrans-2acylCoA-oxidationcontinuesfromthispoint,b-oxidationofamonounsaturatedfattyacid,PolyunsaturatedFattyAcids,SlightlymorecomplicatedSameasforoleicacid,bu

12、tonlyuptoapoint:3cyclesof-oxidationenoyl-CoAisomerase1moreroundof-oxidationtrans-2,cis-4structureisaproblem!2,4-Dienoyl-CoAreductasetotherescue!,Odd-CarbonFattyAcids,-Oxidationyieldspropionyl-CoAOdd-carbonfattyacidsaremetabolizednormally,untilthelastthree-Cfragment-propionyl-CoA-isreachedThreereacti

13、onsconvertpropionyl-CoAtosuccinyl-CoATheinvolvementofbiotinandB12,Whatabout3-Cleftovers?,thecoenzymeB12reaction,Branched-ChainFattyAcids,Analternativeto-oxidationisrequiredBranchedchainFAswithbranchesatodd-numbercarbonsarenotgoodsubstratesfor-oxidation-oxidationisanalternativePhytanicacid-oxidasedec

14、arboxylateswithoxidationatthealphaposition-oxidationoccurspastthebranch,The-oxidationpathwayforphytanicacidoxidation,Peroxisomal-Oxidation,Peroxisomes-organellesthatcarryoutflavin-dependentoxidations,regeneratingoxidizedflavinsbyreactionwithO2toproduceH2O2VLGFAshavetotransportedintotheperoxisomewith

15、thehelpofABCD1(ATPbindingcassettesubfamilyDmember1)andthenbeoxidizedthere.ABCD1mutationcancauseadrenoleukodystrophy(ALD)Similartomitochondrial-oxidation,butinitialdoublebondformationisbyacyl-CoAoxidaseElectronsgotoO2ratherthane-transportFewerATPsresult,ComparisonofMitochondrialandPeroxisomalfattyaci

16、doxidation,KetoneBodies,AspecialsourceoffuelandenergyforcertaintissuesSomeoftheacetyl-CoAproducedbyfattyacidoxidationinlivermitochondriaisconvertedtoacetone,acetoacetateand-hydroxybutyrateThesearecalledketonebodiesSourceoffuelforbrain,heartandmuscleMajorenergysourceforbrainduringstarvationTheyaretra

17、nsportableformsoffattyacids!,KetoneBodies-II,InterestingAspectsofTheirSynthesisOccursonlyinthemitochondrialmatrixFirststepisreversethiolaseSecondreactionmakesHMG-CoAThesereactionsaremitochondrialanaloguesofthe(cytosolic)firsttwostepsofcholesterolsynthesisThirdstep-HMG-CoAlyase-issimilartothereverseo

18、fcitratesynthase,Formationofketonebodies,Utilizationofketonebodiesinextra-hepatictissues,KetoneBodiesandDiabetes,StarvationofcellsinthemidstofplentyGlucoseisabundantinblood,butuptakebycellsinmuscle,liver,andadiposecellsislowCells,metabolicallystarved,turntogluconeogenesisandfat/proteincatabolismInty

19、peIdiabetics,OAAislow,duetoexcessgluconeogenesis,soAc-CoAfromfat/proteincatabolismdoesnotgotoTCA,butrathertoketonebodyproductionAcetonecanbedetectedonbreathoftypeIdiabetics,FattyAcidBiosynthesis,TheBiosynthesisandDegradationPathwaysareDifferentAsincasesofglycolysis/gluconeogenesisandglycogensynthesi

20、s/breakdown,fattyacidsynthesisanddegradationgobydifferentroutesTherearefourmajordifferencesbetweenfattyacidbreakdownandbiosynthesis,TheDifferences,BetweenfattyacidbiosynthesisandbreakdownIntermediatesinsynthesisarelinkedto-SHgroupsofacylcarrierproteins(ascomparedto-SHgroupsofCoASynthesisincytosol;br

21、eakdowninmitochondriaEnzymesofsynthesisareonepolypeptideBiosynthesisusesNADPH/NADP+;breakdownusesNADH/NAD+andFAD/FADH2,Comparisonoffattyacidoxidationandfattyacidbiosynthesis,GeneralFeaturesofFFAbiosynthesis,Cellularlocation-cytosolPrimers-acetyl-CoAActivated2-Cunits-malonyl-CoADecarboxylationofmalon

22、yl-CoAandreducingpowerofNADPHdrivechaingrowthChaingrowsto16-carbonsOtherenzymesadddoublebondsandmoreCs,Challenge:Ac-CoAinCytosol,Whatarethesources?Aminoaciddegradationproducescytosolicacetyl-CoAFAAoxidationproducesmitochondrialacetyl-CoAGlycolysisyieldscytosolicpyruvatewhichisconvertedtoacetyl-CoAin

23、mitochondriaCitrate-malate-pyruvateshuttleprovidescytosolicacetateunitsandreducingequivalentsforfattyacidsynthesis,Thecitrate-malate-pyruvateshuttle,Acetyl-CoACarboxylase,TheACCenzymecommitsacetatetoFAsynthesisCarboxylationofacetyl-CoAtoformmalonyl-CoAistheirreversible,committedstepinfattyacidbiosyn

24、thesisACCusesbicarbonateandATP(andbiotin)E.colienzymehasthreesubunitsAnimalenzymeisonepolypeptidewithallthreefunctions-biotincarboxylcarrier,biotincarboxylaseandtranscarboxylaseMammalianAcetyl-CoACarboxylaseHasTwoMajorIsoforms.TherearetwomajorisoformsofACC.ACC1occursinadiposetissueandACC2occursintis

25、suesthatoxidizebutdonotsynthesizefattyacids,suchasheartmuscle.,Acetyl-CoAcarboxylase-biotintransferscarboxylgroups,Acetyl-CoAcarboxylasereaction,TheAcylCarrierProtein(ACP),Carrierofintermediatesinfattyacidsynthesisa77residueproteininE.coli-withaphosphopantetheinecontaining-SHIntermsoffunction,itsala

26、rgeCoAComparisonofACPandCoA,AcylcarrierproteinandcoenzymeA,FattyAcidSynthesisinAnimals,FattyAcidSynthase-amultienzymecomplexDimerof250kDmultifunctionalpolypeptidestherolesofactivesiteserinesonAT&MTSteps3-6repeattoelongatethechain,MammalianFASynthaseDimer,FirstthreestepsofFAsynthesis,Step45ofFASynthe

27、sis,Step7andRepeatsofFASynthesis,Elongation,beyondthe16-Clengthofpalmitate,occursinmitochondria.Endoplasmicreticulumenzymesalsoyieldlongerfattyacids.Fattyacidelongationwithinmitochondriaoccursviab-oxidationrunninginreverse,exceptthatNADPHservesaselectrondonorforthefinalreductionstep.Desaturation:Mam

28、maliancellshavelimitedabilitytointroducedoublebondsinfattyacids.Someunsaturatedfattyacidsaredietaryessentials,e.g.,linoleicacid,18:2cisD9,12.Mammaliancellscannotcreatedoublebondsatcertainlocations(e.g.,D12).,FattyAcidModification,ElongationandDesaturationofFA,RegulationofFFAOxidation,Rate-limitingen

29、zymesiscarnitinepalmitoyltransferaseI(CPTI)Itisinhibitedbymalonyl-CoAwhenfattyacidsynthesisisstimulated.Thisinhibitionkeepsthenewlysynthesizedfattyacidsoutofthemitochondriaandthusawayfromthe-oxidationsystem.Inheartmuscle,anoxidativetissuethatdoesnotcarryoutfattyacidbiosynthesis,containsACC2,whosesol

30、efunctionappearstobethesynthesisofmalonyl-CoAtoregulatefattyacidoxidation.,Rate-limitingenzymesisACC1ACC1formslong,activefilamentouspolymersfrominactiveprotomersPalmitoyl-CoA(product)favorsmonomersCitratefavorstheactivepolymericformPhosphorylationmodulatescitrateactivationandpalmitoyl-CoAinhibitionAMP-dependentproteinkinase(AMPK),whichphosphorylates(inactivates)ACC,RegulationofFFASynthesis,RegulationofACC1,