清华大学生物化学脂肪分解代谢ppt课件

Chapter17FattyAcidCatabolism 1 Thegoodandbadsidesofusingtriacylglycerolsasanenergystorage Highlyreduced withanenergyofcompleteoxidationmorethantwicethatforthesameweightofcarbohydratesorproteins 38kJ gvs 18kJ g Highlyhydrophobic doesnotraiseosmolarityofcytosol noraddextraweight butmustbeemulsifiedbeforedigestionandtransportedbyspecialproteinsinblood Chemicallyinert noundesiredchemicalreactionswithotherconstituents butmustbeactivated byattachingthecarboxylgrouptocoenzymeA tobreakthestableC Cbonds Fattyacidsisacentralenergysourceinanimals especiallytheliver heart andrestingskeletalmuscle manyprotists andsomebacteria theonlyenergysourceforhibernatinganimalsandmigratingbirds notamajorenergysourceinplants Sourcesforcellstoobtainfattyacids diet storedlipiddroplets synthesizedfromtheexcesscarbohydratesandaminoacidsbysomespecialorgans e g liver 2 Dietarytriacylglycerolsareemulsifiedandabsorbedbytheintestine Bilesalts e g taurocholate牛黄胆酸andglycocholate甘胆酸 synthesizedfromcholesterolinliver emulsifiesmacroscopicfatparticlesintomicroscopicmixedmicellesforbetterlipaseactionandabsorption Fattyacidsgeneratedfromtriacylglycerol catalyzedbytheintestinallipase diffuseintointestinalepithelialcells bereconvertedintotriacylglycerol andpackedwithcholesterolestersandspecificapolipoproteinsinchylomicrons 乳糜微滴 Processingofdietarylipidsinvertebrates Processingofdietarylipidsinvertebrates Molecularstructureofachylomicron Molecularstructureofachylomicron TriacylglycerolsareconvertedintofattyacidsandglycerolsinthecapillariesbytheactionoflipoproteinlipasesactivatedbyapoC IIonchylomicrons whichinturnareabsorbedmainlybyadipocytesandmyocytesforstorageandenergyconsumption Theleftoverofthechylomicrons containingmainlycholesterolandapolipoproteins willbetakenupbytheliverbyendocytosis triacylglycerolswillbeusedastheenergysourceforthelivercells convertedtoketonebodiesortransportedtoadiposetissuesafterbeingpackedwithapolipoproteins 3 Mobilizationofstoredtriacylglycerolsinadipocytesneedshormonetosignalthedemand Thehormonesepinephrineandglucagon signalingalackofglucoseintheblood willbindtoreceptorsonadipocytesurfaceandactivatethehormone sensitivelipaseandperilipinmoleculesonthesurfaceofthelipiddroplets Fattyacidsreleasedarecarriedtoenergy demandingtissues e g skeletalmuscle heart andrenalcortex viathe62kDmonomericserumalbumin eachbindingasmanyas10fattyacids Mobilizationoftriacylglycerolsstoredinadiposetissue Entryofglycerolintotheglycolyticpathway 4 Earlylabelingexperiments 1904 fattyacidsaredegradedbysequentialremovaloftwo carbonunits Whendogswerefedwithodd numberedfattyacidsattachedtoaphenylgroup benzoatewasexcreted andwhenfedwitheven numbered phenylacetatewasexcreted Hypothesis theb carbonisoxidized withtwo carbonunitsreleasedbyeachroundofoxidation Theseexperimentsarealandmarkinbiochemistry inusingsyntheticlabel thephenylgrouphere toelucidatereactionmechanism andwasdonelongbeforeradioisotopeswasusedinbiochemistry FranzKnoop slabelingexperiments 1904 fattyacidsaredegradedbyoxidationatthebcarbon i e boxidation b b a a 5 Fattyacidoxidationwasfoundtooccurinmitochondria Enzymesoffattyacidoxidationinanimalcellswerelocalizedinthemitochondriamatrix RevealedbyEugeneKennedyandAlbertLehningerin1948 6 Fattyacidsareactivatedontheoutermembraneofmitochondria Fattyacidsareconvertedtofattyacyl CoA ahighenergycompound viaafattyacyl adenylateintermediate enzyme bound mixedanhydride bytheactionoffattyacyl CoAsynthetases alsocalledfattyacidthiokinase Pyrophosphateishydrolyzedbyinorganicpyrophosphatase thustwoanhydridebondsofATPareconsumedtoformonehigh energythioesterbond thuspullingthereactionforward acommonphenomenainbiosyntheticreactions Acyl adenylatesareoftenformedwhen COOHgroupsareactivatedinbiochemistry Conversionofafattyacidtoafattyacyl CoA 7 Activated longchain fattyacidsarecarriedintothematrixbycarnitine Thefattyacylgroupisattachedtocarnitine 肉碱 viatransesterificationbytheactionofcarnitineacyltransferaseIlocatedontheoutermembraneofmitochondria formingfattyacyl carnitine leavingtheCoAinthecytosol Theacylcarnitine carnitinetransportermovesacyl carnitineacrosstheinnermembraneofmitochondriaviafacilitateddiffusion Medium chainacyl CoAsseemtoenterthematrixbythemselves withoutbeingcarriedbycarnitine Fattyacidentryintomitochondriaviatheacyl carnitine carnitinetransporter TheacylgroupisthentransferredbacktoCoAtoformfattyacyl CoAbytheactionofcarnitineacyltransferaseIIlocatedontheinnerfaceoftheinnermembrane Thisenteringstepseemstoberate limitingforfattyacidoxidationinmitochondriaanddiseaseshavebeenfoundtobecausedbyadefectofthisstep withachingmusclecramp especiallyduringfasting exerciseorwhenonahigh fatdiet 8 Fattyacyl CoAisoxidizedtoacetyl CoAviamultipleroundsofboxidation Theboxidationconsistsoffourreactions dehydrogenationhydrationdehydrogenationthiolyticcleavage Theb oxidationpathway The1stdehydrogenationiscatalyzedbythemembrane boundacyl CoAdehydrogenase convertingacyl CoAtotrans 2 enoyl CoAwithelectronscollectedbyFADandfurthertransferredintotherespiratorychainviatheelectron transferringflavoprotein ETF alsoboundtotheinnermembraneofthemitochondria Acyl CoAdehydrogenaseexistsinthreeisozymesactingontheacyl CoAsoflong 12 18C medium 4 14C andshort 4 8C chains Thehydrationstep stereospecificallycatalyzedbyenoyl CoAhydratase convertsthetrans 2 enoyl CoAtoL b hydroxylacyl CoA thecisisomercanalsobeconverted buttotheDisomer The2nddehydrogenationiscatalyzedbyL b hydroxylacyl CoAdehydrogenase convertingL b hydroxylacyl CoAtob ketoacyl CoA notactontheDisomer withelectronscollectedbyNAD Theacyl CoAacetyltransferase orcommonlycalledthiolase catalyzesthenucleophilicattackofCoAtothecarbonylcarbon cleavingb ketoacyl CoAbetweentheaandbcarbon thiolysis generatingtwoacyl CoAmoleculeswithoneenteringthecitricacidcycleandtheotherreenteringtheboxidationpathway Thefirstthreereactionsoftheboxidationusedthesamereactionstrategyasthelastthreereactionsinthecitricacidcycle allinvolvingtheoxidationofahighlyreducedcarbon from CH2 to CHO Aconservedreactionsequencetoinduceacarbonylfunctiononthecarbonbtoacarboxylgroup Stagesoffattyacidoxidation Palmitol CoA 7CoA 7FAD 7NAD 7H2O8acetyl CoA 7FADH2 7NADH 7H Thecompleteoxidizationofeach16 carbonpalmitate toH2OandCO2 yields 106ATP 32ATPperglucose bothhavingabout60 ofactualenergyrecovery Palmitoyl CoA 23O2 108Pi 108ADPCoA 108ATP 16CO2 23H2O Hibernatinggrizzlybearsusebodyfatastheirsolefuel 9 Oxidationofunsaturatedfattyacidsrequiresoneortwoauxiliaryenzymes anisomeraseandareductase Theisomeraseconvertsacis 3doublebondtoatrans 2doublebond Thereductase 2 4 dienoyl CoAreductase convertsatrans 2 cis 4structuretoatrans 3structure whichwillbefurtherconvertedtoatrans 2structurebytheisomerase NADPHisneededforthereduction fromtwodoublebondstoone Oxidationofamonounsaturatedfattyacid theenoyl CoAisomerasehelpstorepositionthedoublebond Bothanisomeraseandareductaseareneededforoxidizingapolyunsaturatedfattyacid 10 Propionyl CoAgeneratedfromodd numberfattyacids andthreeaminoacids isconvertedtosuccinyl CoA Odd numberfattyacids commonlyfoundinthelipidsofsomeplantsandmarineorganisms willalsobeoxidizedviatheboxidationpathway butgeneratingapropionyl CoAatthelaststepofthiolysis Propionyl CoAisconvertedtosuccinyl CoAviaanunusualenzymaticpathwayofthreereactions Propionyl CoAcanbeconvertedtosuccinyl CoAviaacarboxylation anepimerizationandanintramoleculargroupshifting Propionyl CoAisfirstcarboxylatedattheacarbontoformD methylmalonyl CoA catalyzedbypropionyl CoAcarboxylase TheD methylmalonyl CoAisthenepimerizedtotheL isomerbytheactionofanepimerase TheL methylmalonyl CoAisthenconvertedtosuccinyl CoAbyanintramolecularrearrangementviafreeradicalintermediates withthecatalysisofmethylmalonyl CoAmutase using5 deoxyadenosylcobalamin orcoenzymeB12 asacoenzyme CoenzymeB12enzymesactinintramolecularrearrangements methylation andreductionofribonucleotidestodeoxynucleotides Perniciousanemia 恶性贫血 iscausedbyafailuretoabsorbvitaminB12 whichmayinturnbecausedbyadeficiencyoftheintrinsicfactor a59kDglycoproteinneededforvitaminB12absorption VitaminB12issynthesizedbyafewintestinalbacteria notplants 3 DstructureofcoenzymeB12andpenicillin 11 Therateofb oxidationinmitochondriaislimitedbytheenteringrateoffattyacyl CoA Fattyacyl CoAinthecytosolcanentermitochondriaforoxidativedegradationorbeconvertedtotriacylglycerolinthecytosolwhenexcessglucoseispresentthatcannotbeoxidizedorstoredasglycogenandisconvertedintofattyacidsforstorage ThekeyregulatoryproteiniscarnitineacyltransferaseI whichisinhibitedbymalonyl CoA thefirstintermediateforfattyacidsynthesisfromacetyl CoA Coordinatedregulationoffattyacidsynthesisandbreakdown 12 Fattyacidoxidationalsooccursinperoxisomes glyoxysomes Peroxisomeistheprincipleorganelleinwhichfattyacidsareoxidizedinplantcells Alsoviathefour stepboxidationpathway buttheelectronscollectedbyFADaredirectlypassedtoO2 producingtheharmfulH2O2 whichisimmediatelyconvertedtoH2OandO2 Energyreleasedisdissipatedasheat notconservedinATP Comparisonofb oxidationinmitochondrionandinperoxisome glyoxysome Theacetyl CoAproducedinanimalperoxisomesistransportedintocytosol whereitisusedinthesynthesisofcholesterolandothermetabolites Theacetyl CoAproducedinplantperoxisomes glyoxysomes especiallyingerminatingseeds isconvertedtosuccinateviatheglyoxylatecycle andthentoglucoseviagluconeogenesis Triacylglycerolsasglucosesourceinseeds Theb oxidationenzymesinmitochondriaandperoxisomesareorganizeddifferently beingseparateenzymesinmitochondria asingram positivebacteria andonecomplexinperoxisomes asingram negativebacteria Boundtotheinnermitochondrialmembrane 13 Acetyl CoAinlivercanbeconvertedtoketonebodieswhencarbohydratesupplyisnotoptimal Underfastingordiabeticconditions oxaloacetateconcentrationinhepatocytewillbelow therateofglycolysisislow thusthesupplyofprecursorsforreplenishingoxaloacetateiscutoff andoxaloacetateissiphonedoffintogluconeogenesis tomaintainbloodglucoselevel Theacetyl CoAgeneratedfromactivefattyacidoxidationcannotbeoxidizedviathecitricacidcycleandwillbeconvertedtoacetoacetate b hydroxylbutyrate andacetone i e theketonebodies 酮体 inmitochondriaforexporttoothertissues Ketonebodyformationandexportfromtheliver Formationofketonebodiesfromacetyl CoA 14 Ketonebodiesareconvertedbacktoacetyl CoAinextrahepatictissues D b hydroxylbutyrateisreoxidizedtoacetoacetate catalyzedbythedehydrogenase Acetoacetateisthenconvertedtoacetoacetyl CoAusingsuccinyl CoA catalyzedbyb ketoacyl CoAtransferase Acetoacetyl CoAiscleavedtotwoacetyl CoA againcatalyzedbythiolase Heart skeletalmuscleandtherenalcortexuseacetoacetateinpreferencetoglucose Thebrainadaptstotheutilizationofacetoacetateduringstarvationanddiabetes b Hydroxybutyratecanbeusedasafuelbyextrahepatictissues Notpresentinliver Overproductionofketonebodiesinuncontrolleddiabetesorseverelyreducedcalorieintakecanleadtoacidosisandketosis Keywords Activationandtransportoffattyacidsb oxidation reactionandregulationKetonebo