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10.LipidmetabolismHuangxiaoLinyiuniversity10.LipidmetabolismHuangxiao1KeynotesStructuresandrolesoffattyacidsFattyacidbreakdownFattyacidsynthesisTriacylglycerolsKeynotesStructuresandroles210.1Structuresandrolesoffattyacids

Fattyacidshavealonghydrocarbonchainwithaterminalcarboxylicacidgroup.Mostfattyacidshaveanevennumberofcarbonatomsinanunbranchedchain.Saturatedfattyacidshavenodoublebondsbetweenthecarbonatoms,whereasmono-andpolyunsaturatedfattyacidshaveoneormoredoublebonds.10.1Structuresandrolesoff3

Stearicacid(b)Stearicacid(b)4Fattyacidshavefourmajorbiologicalroles:1)Theyarecomponentsofmembranes(glycerophospholipidsandsphingolipids)2)Severalproteinsarecovalentlymodifiedbyfattyacids.3)Theyactasenergystores(triacylglycerols)andfuelmolecules.4)Fattyacidderivativesserveashormonesandintracellularsecondmessengers.Fattyacidshavefourmajorbi510.2FattyacidbreakdownOverviewActivationTransportintomitochondriaβ-oxidationpathwayEnergyyieldKetonebodies10.2FattyacidbreakdownOverv61.overviewFattyacidbreakdownbringsabouttheoxidationoflong-chainfattyacids.ThefattyacidsarefirstconvertedtotheiracylcoenzymeAderivativesandthendegradedbythesuccessiveremovaloftwo-carbonunitsfromtheendofthefattyacidasacetylCoA.1.overviewFattyacidbreakdown7

IncytosolAcylCoAsynthetase

2.FattyacidactivationIncytosolAcylCoAsyntheta8

RCOOH+CoA—SHRCO~SCoAAcylCoAsynthetase

ATPAMP+PPiMg2+

H2O2PithereactionisirreversiblefattyacidacylCoARCOOH+CoA—SHRCO~SCoAAcylC93.Transportintomitochondria

longerchainacylCoAsdonotreadilycrosstheinnermitochondrialmembrane,andrequireaspecifictransportmechanism.RCO-SCoACoA-SHtransferase(CH3)3N+-CH2CH-CH2COOHOHcarnitine(CH3)3N+CH2CHCH2COOHRCO-Oacylcarnitine

3.Transportintomitochondria10R-COSCoA

H-SCoAcarnitineR-CO-carnitine

R-CO-carnitine

H-SCoA

carnitine

R-COSCoA

transferaseⅠβ-oxidationtransferaseⅡInnermitochondrialmembraneR-COSCoAH-SCoAcarnitineR-C11Lipid-metabolism(脂類代謝)課件124.β-OxidationpathwayOxidation(byFAD)HydrationOxidation(byNAD+)Thiolysis4.β-OxidationpathwayOxidation13

①

oxidation

acylCoAdehydrogenaseFADFADH2②

hydration

RCH2CCCO~CoAHH

trans2-enoylCoA

enoylCoAhydratase

H2OOHRCH2CHCH2CO~SCoA3-hydroxyacylCoA1.5ATPrespiratorychainＯR-CH2-

CH2C-SCoA||①oxidationacylCoAdehydr14OHRCH2CHCH2CO~SCoA

③

oxidation

NAD+NADH+H+dehydrogenase④

thiolysis

CH3CO~SCoA

RCH2CO~SCoA

（1）（2）（3）（4）3-ketoacylCoARCH2C~SCoAOCH2COCoA-SHketothiolase

2.5ATPrespiratorychain

roundreactionOHRCH2CHCH2CO~SCoA③oxidat15Lipid-metabolism(脂類代謝)課件16

Oxidationofodd-chainfattyacidRacemaseB12CH3-CH2-COCoAPropionylCoAHOOC-CH2-CH2-COCoASuccinylCoAOxidationofodd-RacemaseCH3175.Energyyield(C16:0)

PalmitoylCoA+7FAD+7NAD++7CoA-SH+7H2O→8acetylCoA+7FADH2+7(NADH+H+)5.Energyyield(C16:0)Palmitoy18PalmitoylCoA+7FAD+7CoA+7H2O7Reactioncyclesof-Oxidation8acetylCoA+7FADH2+7(NADH+H+)Summary

2.-oxidation:7FADH2:

10.5(14)ATPsproduced,7(NADH+H+):17.5(21)ATPsproduced,3.Tricarboxylicacidcycleandoxidativephosphorylation8acetylCoA:80(96)ATPsproduced.Total106(129)ATPsproduced1.FrompalmitatetopalmitoylCoAconsumed2ATPs

PalmitoylCoA+7FAD+7CoA196.KetonebodiesAcetoacetate,D-3-hydroxybutytateandacetonearecalledketonebodies.Theyareproducedintheliverandprovideanalternativesupplyoffuelforthebrainunderstarvationconditionsorindiabetes.6.KetonebodiesAcetoacetate,D20Doyouthinkthattheyoungmantakes250gofbutterperdayfor3days?Really!Oh,soStupid!theremustbelotsofketonebodiesinhisurine

Doyouthinkthattheyoungma2110.3FattyacidsynthesisOverviewTransportintothecytosolThepathway10.3FattyacidsynthesisOverv221.Overview

Fattyacidsynthesisinvolvesthecondensationoftwo-carbonunits,intheformofacetylCoA,toformlonghydrocarbonchainsinaseriesofreactions.1.OverviewFattyacidsynthes232.Transportintothecytosol

Sincefattyacidsynthsistakesplaceinthecytosol,theacetylCoAproducedfrompyruvatehastobetransportedoutofthemitochondria.2.Transportintothecytosol

S24citrateoxaloacetatepyruvateH2OATPCO2AcetylCoA

mitochondrioncytosol

citrateoxaloacetateAcetylCoAATP,CoASHADP+Pi

malatepyruvateNADH+H+NAD+NADP+NADPH+H+CO2malate

PyrcarboxylaseFattyacidsynthesiscitrateoxaloacetatepyruvate25

PalmiticacidisthefirstsynthesizedfattyacidfromacetylCoA.Allotherfattyacidsaremadebythemodificationofpalmiticacid.AcetylCoAMalonylCoApalmitateOtherfattyacids①②③

3.ThepathwayPalmiticacidisthefir261）FormationofmalonylCoAmalonylCoAKeyenzymeforpalmitatesynthesis(allostericenzyme)Protomer(inactive)

citrateisocitratepalmitoylCoAlongchainacylCoAPolymer(active)(10-70protomer)

1）FormationofmalonylCoAmalo27

CH3-C～SCOA=OCH3-C～ACP=O

COA-SHACP-SHAcetyltransacylaseHOOC-CH2-C～SCOA+ACP-SH

HOOC-CH2-C～ACPO=Malonyl-ACP

O=+COA-SHCH3-C～SCOA=OCH3-C～ACP=O28CondensationCH3-C～ACP+=OHOOC-CH2-C～ACPO=

condensingenzymeCH3-C-CH2-C～ACPO=O=+CO2ReductionCH3-C-CH2-C～SACPO=O=+NADPH++

H+

reductaseCH3-CH-CH2-C～ACPO-OH=+NADP+

CondensationCH3-C～ACP+=O29DehydrationCH3-CH-CH2-C～ACPO

︱OH==-C-C==CO-CH3-HH～ACP

dehydratase+H2O

Reduction-C==CO-CH3HH～ACPC-=-

32+NADPH+H+

reductaseCH3-CH2-CH-C～ACPO=+NADP+

C==CO-CH3-HH

DehydrationCH3-CH-CH2-C～A30ComparisonbetweenCoAandACPComparisonbetweenCoAandACP31Thecomparisonbetweensynthesisofpalmitateand-oxidationoffattyacidsynthesisofpalmitate-oxidationoffattyacid

1.Locationcytosolmitochondrialmatrix2.LinkedtoacylcarrierproteinCoA

with4-phosphopantetheinewith4-phosphopantetheine3.EnzymesacetylCoAcarboxylase4enzymesfattyacidsynthetase(multifunctionalenzyme)4.2CstwocarbonsfromreleasetwocarbonsasmalonylCoAacetylCoA5.CoenzymesNADPHNAD+,FAD6.ProductpalmitateacetylCoAThecomparisonbetweensynthes3210.4Triacylglycerols

10.4Triacylglycerols33

1.breakdownoftriacylglycerollipaseslipaseslipases1.breakdownoftriacylglyc34

2.OxidationofGlycerol(Glycerolcanbemetabolizedintheliver,kidney,andintestine,butnotinadiposetissueandskeletalmuscle)end2.OxidationofGly35GCH2OHC=OCH2O-PNADH+H+NAD+Glycerol-3-PdehydrogenaseCH2OHCCH2O-HO—PCH2OCOR1CCH2O-R2CO-O—PCH2OCOR1CCH2OHR2CO-O-H2OPi

CH2OCOR1CCH2OCOR3R2CO-O—CoA-SHR3CO~SCoA

R1CO~SCoAR2CO~SCoAacyltransferase2CoA-SHphosphatidicacid

3.synthesisoftriacylglycerolsGCH2OHC=OCH2O-PNADH+H+NAD+G36Problem

Whatarethedifferencesbetween-oxidationandbiosynthesisoffattyacid?Describetheprocessesof-oxidation.ProblemWhatarethedifferenc3710.LipidmetabolismHuangxiaoLinyiuniversity10.LipidmetabolismHuangxiao38KeynotesStructuresandrolesoffattyacidsFattyacidbreakdownFattyacidsynthesisTriacylglycerolsKeynotesStructuresandroles3910.1Structuresandrolesoffattyacids

Fattyacidshavealonghydrocarbonchainwithaterminalcarboxylicacidgroup.Mostfattyacidshaveanevennumberofcarbonatomsinanunbranchedchain.Saturatedfattyacidshavenodoublebondsbetweenthecarbonatoms,whereasmono-andpolyunsaturatedfattyacidshaveoneormoredoublebonds.10.1Structuresandrolesoff40

Stearicacid(b)Stearicacid(b)41Fattyacidshavefourmajorbiologicalroles:1)Theyarecomponentsofmembranes(glycerophospholipidsandsphingolipids)2)Severalproteinsarecovalentlymodifiedbyfattyacids.3)Theyactasenergystores(triacylglycerols)andfuelmolecules.4)Fattyacidderivativesserveashormonesandintracellularsecondmessengers.Fattyacidshavefourmajorbi4210.2FattyacidbreakdownOverviewActivationTransportintomitochondriaβ-oxidationpathwayEnergyyieldKetonebodies10.2FattyacidbreakdownOverv431.overviewFattyacidbreakdownbringsabouttheoxidationoflong-chainfattyacids.ThefattyacidsarefirstconvertedtotheiracylcoenzymeAderivativesandthendegradedbythesuccessiveremovaloftwo-carbonunitsfromtheendofthefattyacidasacetylCoA.1.overviewFattyacidbreakdown44

IncytosolAcylCoAsynthetase

2.FattyacidactivationIncytosolAcylCoAsyntheta45

RCOOH+CoA—SHRCO~SCoAAcylCoAsynthetase

ATPAMP+PPiMg2+

H2O2PithereactionisirreversiblefattyacidacylCoARCOOH+CoA—SHRCO~SCoAAcylC463.Transportintomitochondria

longerchainacylCoAsdonotreadilycrosstheinnermitochondrialmembrane,andrequireaspecifictransportmechanism.RCO-SCoACoA-SHtransferase(CH3)3N+-CH2CH-CH2COOHOHcarnitine(CH3)3N+CH2CHCH2COOHRCO-Oacylcarnitine

3.Transportintomitochondria47R-COSCoA

H-SCoAcarnitineR-CO-carnitine

R-CO-carnitine

H-SCoA

carnitine

R-COSCoA

transferaseⅠβ-oxidationtransferaseⅡInnermitochondrialmembraneR-COSCoAH-SCoAcarnitineR-C48Lipid-metabolism(脂類代謝)課件494.β-OxidationpathwayOxidation(byFAD)HydrationOxidation(byNAD+)Thiolysis4.β-OxidationpathwayOxidation50

①

oxidation

acylCoAdehydrogenaseFADFADH2②

hydration

RCH2CCCO~CoAHH

trans2-enoylCoA

enoylCoAhydratase

H2OOHRCH2CHCH2CO~SCoA3-hydroxyacylCoA1.5ATPrespiratorychainＯR-CH2-

CH2C-SCoA||①oxidationacylCoAdehydr51OHRCH2CHCH2CO~SCoA

③

oxidation

NAD+NADH+H+dehydrogenase④

thiolysis

CH3CO~SCoA

RCH2CO~SCoA

（1）（2）（3）（4）3-ketoacylCoARCH2C~SCoAOCH2COCoA-SHketothiolase

2.5ATPrespiratorychain

roundreactionOHRCH2CHCH2CO~SCoA③oxidat52Lipid-metabolism(脂類代謝)課件53

Oxidationofodd-chainfattyacidRacemaseB12CH3-CH2-COCoAPropionylCoAHOOC-CH2-CH2-COCoASuccinylCoAOxidationofodd-RacemaseCH3545.Energyyield(C16:0)

PalmitoylCoA+7FAD+7NAD++7CoA-SH+7H2O→8acetylCoA+7FADH2+7(NADH+H+)5.Energyyield(C16:0)Palmitoy55PalmitoylCoA+7FAD+7CoA+7H2O7Reactioncyclesof-Oxidation8acetylCoA+7FADH2+7(NADH+H+)Summary

2.-oxidation:7FADH2:

10.5(14)ATPsproduced,7(NADH+H+):17.5(21)ATPsproduced,3.Tricarboxylicacidcycleandoxidativephosphorylation8acetylCoA:80(96)ATPsproduced.Total106(129)ATPsproduced1.FrompalmitatetopalmitoylCoAconsumed2ATPs

PalmitoylCoA+7FAD+7CoA566.KetonebodiesAcetoacetate,D-3-hydroxybutytateandacetonearecalledketonebodies.Theyareproducedintheliverandprovideanalternativesupplyoffuelforthebrainunderstarvationconditionsorindiabetes.6.KetonebodiesAcetoacetate,D57Doyouthinkthattheyoungmantakes250gofbutterperdayfor3days?Really!Oh,soStupid!theremustbelotsofketonebodiesinhisurine

Doyouthinkthattheyoungma5810.3FattyacidsynthesisOverviewTransportintothecytosolThepathway10.3FattyacidsynthesisOverv591.Overview

Fattyacidsynthesisinvolvesthecondensationoftwo-carbonunits,intheformofacetylCoA,toformlonghydrocarbonchainsinaseriesofreactions.1.OverviewFattyacidsynthes602.Transportintothecytosol

Sincefattyacidsynthsistakesplaceinthecytosol,theacetylCoAproducedfrompyruvatehastobetransportedoutofthemitochondria.2.Transportintothecytosol

S61citrateoxaloacetatepyruvateH2OATPCO2AcetylCoA

mitochondrioncytosol

citrateoxaloacetateAcetylCoAATP,CoASHADP+Pi

malatepyruvateNADH+H+NAD+NADP+NADPH+H+CO2malate

PyrcarboxylaseFattyacidsynthesiscitrateoxaloacetatepyruvate62

PalmiticacidisthefirstsynthesizedfattyacidfromacetylCoA.Allotherfattyacidsaremadebythemodificationofpalmiticacid.AcetylCoAMalonylCoApalmitateOtherfattyacids①②③

3.ThepathwayPalmiticacidisthefir631）FormationofmalonylCoAmalonylCoAKeyenzymeforpalmitatesynthesis(allostericenzyme)Protomer(inactive)

citrateisocitratepalmitoylCoAlongchainacylCoAPolymer(active)(10-70protomer)

1）FormationofmalonylCoAmalo64

CH3-C～SCOA=OCH3-C～ACP=O

COA-SHACP-SHAcetyltransacylaseHOOC-CH2-C～SCOA+ACP-SH

HOOC-CH2-C～ACPO=Malonyl-ACP

O=+COA-SHCH3-C～SCOA=OCH3-C～ACP=O65CondensationCH3-C～ACP+=OHOOC-CH2-C～ACPO=

condensingenzymeCH3-C-CH2-C～ACPO=O=+CO2ReductionCH3-C-CH2-C～SACPO=O=+NADPH++

H+

reductaseCH3-CH-CH2-C～ACPO-OH=+NADP+

CondensationCH3-C～ACP+=O66DehydrationCH3-CH-CH2-C～ACPO

︱OH==-C-C==CO-CH3-HH～ACP

dehydratase+H2O

Reduction-C==CO-CH3HH～ACPC-=-

32+NADPH+H+

reductaseCH3-CH2-CH-C～ACPO=+NADP+

C==CO-CH3-HH

DehydrationCH3-CH-CH2-C～A67ComparisonbetweenCoAandACPComparisonbetweenCoAandACP68Thecomparisonbetweensynthesisofpalmitateand-oxidationoffattyacidsynthesisofpalmitate-oxidationoffattyacid

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