Chapter27 Glycogen metabolism.ppt

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1、Chapter27Glycogenmetabolism,Outline,GlycogenBreakdownGlycogenSynthesisRegulationofGlycogenMetabolism,Glycogen,Glycogenservesasstoragecarbohydrateinanimals,insectsandfungiHeavilybranchedtoallowrapidmobilizationofGlc,Musclescannotmobilizefatasrapidlyasglycogen.Fattyacidresiduesoffatcannotbemetabolized

2、anaerobically.AnimalscannotconvertfattyacidstoGlc,sofatmetabolismalonecannotadequatelymaintainessentialbloodGlclevels.,Whyuseglycogenforenergystorage?,GlycogenBreakdownRequiresThreeEnzymes,A.Glycogenphosphorylasetocleavea1,4linkages,Glycogen+Pi-Glycogen+Glc-1-Pnresiduesn-1residues,B.Glycogendebranch

3、ingenzymea(1-4)glycosyltransferaseanda(1-6)glucosidaseactivities-Glc-1-PandGlc,C.Phosphoglucomutasetoconverttousableform,Glc-1-P-Glc-6-P,Glc-6-phosphataseisrequiredforexportfromliverasGlc,GlycogenPhosphorylase,Dimerofidentical97kDasubunitsStructuralDomainsandBindingSitesEachphosphorylasesubunithasN-

4、andC-terminaldomains.AllostericeffectorbindingsitesandmodificationsitesareintheN-terminaldomain.CofactorislinkedintheC-terminaldomain.ThecatalyticsiteislocatedattheinterfaceofglycogenbindingsubdomainandregulatorydomainwiththeC-terminaldomain.PyridoxalPhosphateisanEssentialCofactorforPhosphorylasePyr

5、idoxal-5-phosphate(PLP),avitaminB6derivative,iscovalentlylinkedtophosphorylaseviaaSchiffbasetoLys679.Inanunusualrole,onlythephosphategroupparticipatesinthecatalyticprocess.,3DStructureModelofGlycogenPhosphorylase,PLPcovalentlyboundtophosphorylaseviaaSchiffbasetoK679,Glycogenphosphorylasereactionmech

6、anism,FormationofanEPiglycogenternarycomplexOxoniumionintermediate(I)formationfromthe-linkedterminalglucosylresidueinvolvingacidcatalysisbyPifacilitatedbyprotontransferfromPLP.ReactionofPiwithoverallretentionofconfigurationaroundC1toform-D-Glc-1-phosphate.Theglycogen,minusoneresidue,cyclesbacktostep

7、1.,ReactionmechanismofGlycogenphosphorylase,Thereactionscatalyzedbydebranchingenzyme,Twoactivesitesfortwodifferentcatalyticactivities-abifunctionalenzymeActsasan(14)transglycosylase(glycosyltransferase)bytransferringan(14)linkedtrisaccharideunitfroma“limitbranch”ofglycogentothenonreducingendofanothe

8、rbranch.Alsocatalyzesthehydrolysisofthe(16)bondoftheremainingglycosylresiduetoyieldGlc.RequiredfordegradationofalmosthalfofglycogenmoleculeMaximalrateofdebranchingenzymemuchslowerthanthatofglycogenphosphorylase,GlycogenDebranchingEnzyme,Phosphoglucomutase,Mechanismofactionissimilartothatofphosphogly

9、ceratemutaseexceptSercarriesphosphorylgrouphere.,IfGlc-1,6-bisPdissociates,enzymeinactivated;smallamountsaregeneratedbyphosphoglucokinasefromGlc-1-Ptopreventinactivation,GlycogenSynthesis,GlucosemustbeactivatedintoUDP-GlcNotice:ADP-GlcforStarch;GDP-GlcorUDP-GlcforCelluloseTheprimer(Glycogenin)isrequ

10、iredProceedfromthereducingendtothenon-reducingendGlycogensynthaseandGlycogenbranchingenzyme,UDP-GlucosePyrophosphorylaseconvertsUTPandGlc-1-PtoUDP-Glcandpyrophosphate.InorganicpyrophosphataseconvertsPPito2Pi,drivingreaction,UDP-GlcSynthesis,UDP-GlcSynthesis,UDPGs“high-energy”statuspermitsittodonateg

11、lucosylunitstothegrowingglycogenchaininathermodynamicallyfavorablereaction.Thisisacommonstrategyforcarbohydrateaddition.,UseofUDP-Glcmakessynthesisreactionfavorable,TheoverallreactionfortheformationofUDPGishighlyexergonic,Glcisaddedina1,4linkagefromUDP-Glctothenon-reducingendofaglycogenchainThereact

12、ionmechanismisapparentlylikethatofphosphorylaseGlycogensynthasecanonlyextendachain-cannotinitiatedenovosynthesis,Glycogensynthase,Thereactioncatalyzedbyglycogensynthase,Glycogenin,Howisglycogensynthesisinitiated?ThefirststepisattachmentofaGlcresiduetoTyr194-OHgroupoftheglycogeninproteinbyatyrosinegl

13、ucosyltransferase.Glycogeninautocatalyticallyextendstheglucanchainbyupto7additionalUDP-Glc-suppliedresidues,formingaprimerfortheinitiationofglycogensynthesis.Onceprimerstarted,glycogensynthasecanassociatetoformternarycomplex;uponextensionofthechain,glycogenindissociatesfromthecomplex,Roleofglycogeni

14、n,Thebranchingofglycogen,Donorfromabranchatleast11residueslong,Newbranchatleast4residuesfromanotherbranch,RegulationofGlycogenMetabolism,GlycogenPhosphorylaseAllostericcontrol(AMP,ATP,G-6-P)Covalentmodification(phosphorylation,dephosphorylation)GlycogenSynthaseAllostericcontrol(G-6-P)Covalentmodific

15、ation(phosphorylation,dephosphorylation),GlycogenPhosphorylaseIsActivatedbyPhosphorylation,RegulationofGlycogenbreakdown,Tstate:activesiteblockedbyloop;Arg569lessavailableforsubstratebindingRstate:rotationofsubunitstoachievemorefavorablepacking;loopdisorderedsoactivesiteaccessible;Arg569rotatedsothataffinityforsubstrateincreased,Conformationalchangesinglycogenphosphorylase,Conformationalchangesinglycogenphosphorylase,Controlofglycogenmetabolisminmuscle,Regulationofphosphoproteinphosphatase-1inmuscle,