脂肪酸的代谢

脂肪酸的代谢第1页/共55页第2页/共55页Someofthefattyacidsreleasedintothebloodareusedforenergy(inmuscle,forexample),andsomearetakenupbytheliverandusedintriacylglycerolsynthesis.Thetriacylglycerolformedintheliveristransportedinthebloodbacktoadiposetissue,wherethefattyacidisreleasedbyextracellularlipoproteinlipase,takenupbyadipocytes,andreesterifiedThetriacylglycerolcycle.Inmammals,triacylglycerolmoleculesarebrokendownandresynthesizedinatriacylglycerolcycleduringstarvation.Someofthefattyacidsreleasedbylipolysisoftriacylglycerolinadiposetissuepassintothebloodstream,andtheremainderareusedforresynthesisoftriacylglycerol.第3页/共55页

Insulinstimulatesconversionofdietarycarbohydratesandproteinstofat.Individualswithdiabetesmellituslackinsulin;inuncontrolleddisease,thisresultsindiminishedfattyacidsynthesis,andtheacetyl-CoAarisingfromcatabolismofcarbohydratesandproteinsisshuntedinsteadtoketonebodyproduction.Peopleinsevereketosissmellofacetone,sotheconditionissometimesmistakenfordrunkenness.Regulationoftriacylglycerolsynthesisbyinsulin第4页/共55页Glyceroneogenesis.Thepathwayisessentiallyanabbreviatedversionofgluconeogenesis,frompyruvatetodihydroxyacetonephosphate(DHAP),followedbyconversionofDHAPtoglycerol3-phosphate,whichisusedforthesynthesisoftriacylglycerol.第5页/共55页Regulationofglyceroneogenesis.(a)Glucocorticoidhormonesstimulateglyceroneogenesisandgluconeogenesisintheliver,whilesuppressingglyceroneogenesisintheadiposetissue(byreciprocalregulationofthegeneexpressingPEPcarboxykinase(PEPCK)inthetwotissues);thisincreasesthefluxthroughthetriacylglycerolcycle.Theglycerolfreedbythebreakdownoftriacylglycerolinadiposetissueisreleasedtothebloodandtransportedtotheliver,whereitisprimarilyconvertedtoglucose,althoughsomeisconvertedtoglycerol3-phosphatebyglycerolkinase.第6页/共55页Thiazolidinedionesactivateanuclearreceptorcalledperoxisomeproliferator-activatedreceptorγ(PPARγ),whichinducestheactivityofPEPcarboxykinase.Therapeutically,thiazolidinedionesincreasetherateofglyceroneogenesis,thusincreasingtheresynthesisoftriacylglycerolinadiposetissueandreducingtheamountoffreefattyacidintheblood.(b)Aclassofdrugscalledthiazolidinedionesarenowusedtotreattype2diabetes.Inthisdisease,highlevelsoffreefattyacidsinthebloodinterferewithglucoseutilizationinmuscleandpromoteinsulinresistance.第7页/共55页2.真核细胞中磷脂的合成Twogeneralstrategiesforformingthephosphodiesterbondofphospholipids.Inbothcases,CDPsuppliesthephosphategroupofthephosphodiesterbond.第8页/共55页Initially,aheadgroup(eitherserineorglycerol3-phosphate)isattachedviaaCDPdiacylglycerolintermediate.Forphospholipidsotherthanphosphatidylserine,theheadgroupisfurthermodified,asshownhere.Intheenzymenames,PGrepresentsphosphatidylglycerol;PS,phosphatidylserine.OriginofthepolarheadgroupsofphospholipidsinE.coli第9页/共55页Theseglycero-phospholipidsaresynthesizedusingstrategy1.Phospha-tidylglycerolissynthesizedasinbacteria.PIrepresentsphospha-tidylinositol.Synthesisofcardiolipinandphosphatidylinositolineukaryotes第10页/共55页The“salvage”pathwayfromphosphatidylserinetophosphatidylethanolamineandphosphatidylcholineinyeast.Phosphatidylserineandphosphatidylethanolamineareinterconvertedbyareversiblehead-groupexchangereaction.Inmammals,phosphatidylserineisderivedfromphosphatidylethanolaminebyareversalofthisreaction;adoMetisS-adenosylmethionine;adoHcy,Sadenosylhomocysteine.第11页/共55页Pathwayforphosphatidylcholinesynthesisfromcholineinmammals.Thesamestrategyshownhere(strategy2)isalsousedforsalvagingethanolamineinphosphatidylethanolaminesynthesis.第12页/共55页Summaryofthepathwaystophosphatidyl-cholineandPhosphatidyl-ethanolamine.Conversionofphosphatidyl-ethanolaminetophosphatidyl-cholineinmammalstakesplaceonlyintheliver.第13页/共55页真核细胞中磷脂的合成（综合1）第14页/共55页真核细胞中磷脂的合成（综合2）第15页/共55页哺乳动物磷脂酰胆碱和磷脂酰乙醇氨的相互转化第16页/共55页真核细胞中CDP-二酰甘油是合成磷脂酰肌醇，磷脂酰甘油，心磷脂的前体。第17页/共55页3.动物细胞中缩醛磷脂的合成第18页/共55页血小板活化因子:1-烷基-2-乙酰甘油磷酸胆碱的合成第19页/共55页4.鞘脂的生物合成由3-酮鞘氨醇合成酶催化的反应开始3-酮鞘氨醇二氢鞘氨醇N-脂酰二氢鞘氨醇神经酰胺第20页/共55页动物细胞中糖基神经酰胺，神经节苷脂和鞘磷脂的由神经酰胺合成。鞘磷脂第21页/共55页5.花生四烯酸是合成前列腺素，血拴烷和白三烯的前体。第22页/共55页前列腺素内过氧化物合成酶催化PGH2的合成第23页/共55页阿斯匹林使环加氧酶失活第24页/共55页5.胆固醇的合成第25页/共55页甲羟戊酸的合成第26页/共55页甲羟戊酸合成的机制第27页/共55页HMG-CoA还原酶的活力受合成速度、降解速度及磷酸化和脱磷酸调控。第28页/共55页甲羟戊酸到鲨烯的转化第29页/共55页第30页/共55页第31页/共55页OxidationatC-15convertsretinoltothealdehyde,retinal(c),andfurtheroxidationproducesretinoicacid(d),ahormonethatregulatesgeneexpression.Retinalcombineswiththeproteinopsintoformrhodopsin(notshown),avisualpigmentwidespreadinnature.Inthedark,retinalofrhodopsinisinthe11-cisform(c).Whenarhodopsinmoleculeisexcitedbyvisiblelight,the11-cis-retinalundergoesaseriesofphotochemicalreactionsthatconvertittoall-trans-retinal(e),forcingachangeintheshapeoftheentirerhodopsinmolecule.Thistransformationintherodcellofthevertebrateretinasendsanelectricalsignaltothebrainthatisthebasisofvisualtransduction.(a)β-CaroteneistheprecursorofvitaminA1.Isoprenestructuralunitsaresetoffbydashedredlines.Cleavageof-caroteneyieldstwomoleculesofvitaminA1(retinol)(b).

VitaminA1anditsprecursorandderivatives第32页/共55页第33页/共55页由鲨烯转化为胆固醇豆甾醇麦角甾醇第34页/共55页

胆固醇的合成是一个高度耗能的过程，合成一个胆固醇需18个乙酰辅酶A，36个ATP，16个NADPH。能源物质过剩时，胆固醇的合成速度加快，午夜时，合成速度较快，膳食固醇类，特别是植物固醇可抑制胆固醇的合成。第35页/共55页第36页/共55页Lipoproteins.(a)Structureofalow-densitylipoprotein(LDL).ApolipoproteinB-100(apoB-100)isoneofthelargestsinglepolypeptidechainsknown,with4,636aminoacidresidues(Mr513,000).(b)Fourclassesoflipoproteins,visualizedintheelectronmicroscopeafternegativestaining.Clockwisefromtopleft:chylomicrons,50to200nmindiameter;VLDL,28to70nm;HDL,8to11nm;andLDL,20to25nm.脂类是由脂蛋白运输的第37页/共55页第38页/共55页Lipoproteinsandlipidtransport.(a)Lipidsaretransportedinthebloodstreamaslipoproteins,whichexistasseveralvariantsthathavedifferentfunctions,differentproteinandlipidcompositions,andthusdifferentdensities.Dietarylipidsarepackagedintochylomicrons;muchoftheirtriacylglycerolcontentisreleasedbylipoproteinlipasetoadiposeandmuscletissuesduringtransportthroughcapillaries.Chylomicronremnants(containinglargelyproteinandcholesterol)aretakenupbytheliver.EndogenouslipidsandcholesterolfromtheliveraredeliveredtoadiposeandmuscletissuebyVLDL.ExtractionoflipidfromVLDL(alongwithlossofsomeapolipoproteins)graduallyconvertssomeofittoLDL,whichdeliverscholesteroltoextrahepatictissuesorreturnstotheliver.ThelivertakesupLDL,VLDLremnants,andchylomicronremnantsbyreceptor-mediatedendocytosis.ExcesscholesterolinextrahepatictissuesistransportedbacktotheliverasHDL.Intheliver,somecholesterolisconvertedtobilesalts.第39页/共55页(b)Bloodplasmasamplescollectedafterafast(left)andafterahigh-fatmeal(right).Chylomicronsproducedafterafattymealgivetheplasmaamilkyappearance.第40页/共55页第41页/共55页Reactioncatalyzedbylecithin-cholesterolacyltransferase(LCAT).ThisenzymeispresentonthesurfaceofHDLandisstimulatedbytheHDLcomponentapoA-I.CholesterylestersaccumulatewithinnascentHDLs,convertingthemtomatureHDLs.第42页/共55页载脂蛋白在肝细胞内质网合成，在内质网组装成脂蛋白颗粒，在高尔基体加工，包装成分泌小泡，分泌到肝细胞外。第43页/共55页脂蛋白颗粒的胞吞和降解第44页/共55页LDL受体的结构第45页/共55页SREBPactivation.Sterolregulatoryelement-bindingproteins(SREBPs,showningreen)areembeddedintheERwhenfirstsynthesized,inacomplexwiththeproteinSREBPcleavage-activatingprotein(SCAP,red).(NandCrepresenttheaminoandcarboxylterminio