生物化学英文版课件：Chapter 21 II Lipid Biosynthesis II

LipidBiosynthesisIIBiosynthesisoffattyacidsandeicosanoids2. Biosynthesisofotherlipids

a.

Triacyloglycerols b.Membranephopholipids c.Cholesterol,steroidsandisoprenoidsFattyacidstriacylglycerols（三脂酰甘油）glycerolphospholipidssphingolipidsBiologicalmembranescholesterolSteroidhormonesarachidonatederivates脂肪酸胆固醇花生四烯酸衍生物生物膜类固醇激素BiosynthesisoftriacylglycerolsBothtriacylglycerolsandglycerophospholipidsaresynthesizedfromphosphatidicacid;Phosphatidicacid(磷脂酸,keyintermediateforlipidbiosynthesis)Acyl-CoAsynthetaseBiosynthesisofPhosphatidicAcidDHAPGlycerolkinaseAcyltransferaseAcyltransferaseAcyl-CoAsynthetase磷脂酸PhosphatidicacidistheprecursorofbothtriacylglycerolsandglycerophospholipidsRegulationoftriacylglycerolbyinsulinTriacylglycerolCycleIsthisafutilecycle(无效循环)?75%ofallfattyacidsreleasedbylipolysisarereesterifiedtoformTGsratherthanusedforfuel!AmJPhysiolEndocrinolMetab258:E382-E389,1990Roleoftriglyceride-fattyacidcycleincontrollingfatmetabolisminhumansduringandafterexerciseFivenormalvolunteerswereinfusedwith[1-13C]palmitateandD-5-glycerolthroughoutrest;4hoftreadmillexerciseat40%maximumO2consumption,and2hofrecovery.

Totalfatoxidationwasquantifiedbyindirectcalorimetry.Lipolysisincreasedfrom2.1to6.0(

mol.kg-1min-1)after30minofexercise,andincreased10.5after4h.Lipolysisdecreasedrapidlyduringthefirst20minofrecovery.75%ofreleasedfattyacidswerereesterifiedatrest.

Triglyceride-fattyacidcyclingplaysanimportantroleinenablingarapidresponseoffattyacidmetabolismtomajorchangesinenergymetabolism.

ThereleasedFAistakenupbyanumberoftissues(eg.muscle)whereitisoxidizedtoprovideenergy.MuchoftheFAtakenbyliverisnotoxidizedandisrecycledtoTGsandreturnedtoadiposetissue.Thisphenomenacouldrepresentanenergyreserveinbloodstreamduringfasting.TheconstantrecyclingofTGsinadiposetissueevenduringstarvationraisesaquestion:

whereisthesourceoftheglycerol?

(glycolysisissuppressedunderstarvation!)

Adiposetissue

generatesG3Pbyglyceroneogenesisashortenedversionofgluconeogenesis,discoveredin1960.

glucoseisnotsynthesizedinadiposetissue.RegulationofGlyceroneogenesisFAsinbloodinterferewithglucoseutilizationinmusclediabetestype2(treatedbyThiazolinediones,噻唑烷二酮).Glucocorticoidhormones

stimulateglyceroneogenesisandgluconeogenesisinliver,butsuppressingglyceroneogenesis

inadiposetissue(reciprocallyregulated).Asaresult,morefreeFAsarereleasedintotheblood.Thiazolidinedionesareusedtotreattype2diabetes(insulinresistance).Thisdrugactivatesperoxisomeproliferator-activatedreceptor

(PPAR

),whichinducestheactivityofPEPcarboxykinase.Therapeutically,thedrugincreasestherateofglyceroneogenesisinadiposetissueandreducingtheamountoffreeFAsintheblood.XPhospholipids(structurallipidsinmembrane）:

Glycerophospholipids SphingolipidsPhosphatidicacid+HeadgroupThephospholipidheadgroupisattachedtoadiacylglycerolbyaphosphodiesterbond,formedwhenphosphoricacidcondenseswithtwoalcohols,eliminatingtwomoleculesofH2O.Headgroup

TwostrategiesforsynthesisofglycerophospholipidsGlycerophospholipidsinE.coli：phosphatidylethanolamine，phosphatidylglycerol，cardiolipin(diphosphatidylglycerol)Glycerophospholipidsineukaryotes:（biosynthesis：ERandGolgicomplex）

phosphatidylethanolamine（脑磷脂），phosphatidylcholine（lecithin,卵磷脂），phosphatidylinositol；

（biosynthesis：innermembraneofmitochondriaphosphatidylglycerol,cardiolipin)CDP-diacylglycerolBiosynthesisofglycerolipidsin

E.coli

BiosynthesisofcardiolipinandphosphatidylinositolineukaryoteDifferencefromE.colisystem:2xphosphatidylglycerolThemajorpathfromphosphatidylserinetophosphatidylethanolamineandphosphatidylcholineinalleukaryotesPathwaysforphosphatidylserinesynthesisviatheheadgroupexchange

inmammalsPSS1:Ca2+-dependentphosphatidylserinesynthasePathwaysforphosphatidylcholinesynthesisinmammals(salvageofcholine)Phosphatidylcholine(lecithin,卵磷脂)Cholineisalipotropic(亲脂)substancewhichfunctionsinthebody'smetabolismasanagentthataidsinthedigestionoffats.Additionally,it-helpsbodytoburnfat;-lowersbloodcholesterol;-asufficientintakeofcholine(vialecithin)

positiveeffectonmentalfunctionsbecauseacetylcholineisaneurotransmitter;-helpstheabsorptionoffatsolublevitamins;-InEurope,ithasbeenusedtotreathepatitis,

alcoholichepatitisandcirrhosisoftheliver

SummaryofthepathwaystosynthesisofmajorphospholipidsonlyinliverBiosynthesisandtransportofglycerophospholipidsCERT:ceramidetransportSynthesisofPlasmalogen-Foundintheplasmamembranesofalleukaryoticcells-Itsconcentrationishighestinthecellsofthecentralnervoussystem;-Thebackboneofasphingolipidissphingosine;-Thesphingosinebackboneofspingolipidsisderivedfrom

palmitoyl-CoAandserine-TheenzymecatalyzingthisreactionrequirespyridoxalphosphateSphingolipidBiosynthesisSphingosine-1-phosphate(S1P):anenigmaticsignallinglipidNatureRev.Mol.CellBiol.2003,4:397CholesterolBiosynthesis

PathwaysubstantiallyactiveonlyinlivercellsAllcarbonatomsarisefromacetyl-CoASqualene,C30linearhydrocarbon,isanintermediateSqualeneisformedfrom5carbonunits(isoprene)All27carbonsincholesterolcanbetracedtoatwo-carbonprecursor-

acetateThecarbonoriginsofcholesterolasrevealedbyradioisotopelabelingstudiesThebriefbiosynthesispathwayandfatesofcholesterolBiosynthesisofcholesterol:StageIisthesynthesisofisopentenylpyrophosphate,anactivatedisopreneunitthatisthekeybuildingblockofcholesterol.

2.StageIIisthecondensationofsixmoleculesofisopentenylpyrophosphatetoformsqualene.

3.InstageIII,squalenecyclizesinanastoundingreactionandthetetracyclicproductissubsequentlyconvertedintocholesterol.

Thebriefbiosynthesispathwayofcholesterol1.FormationofmevalonateThecommittingstepforcholesterolbiosynthesis甲羟戊酸2.Mevalonateto

squalene3.SqualenetocholesterolBiosynthesisofcholesterolLynenFeodorKonradBlochMichaelBrownJosephGoldsteinJohnCornforthGeorgePopjákRegulationofHMG-CoAReductaseasrate-limitingstep,itistheprincipalsiteofregulationincholesterolsynthesisPhosphorylationbycAMPdependentkinaseinactivatesHMG-CoAreductase2.Half-lifeofHMG-CoAreductaseis3hoursanddependsoncholesterollevel3.Geneexpression(mRNAproduction)iscontrolledbycholesterollevelsSynthesisof

cholesterol

isregulatedtocomplementdietaryintake(maintainingacholesterolhomeostasis)HMG-CoAreductasealongwithothergenesencodingenzymesinvolvedincholesterolsynthesisiscontrolledbyafamilyofSREBPs(sterolregulatoryelement-bindingproteins)SREBPactivationSCAP:SREBPcleavage-activatingprotein[sterol]

[sterol]

Statins(他汀类药物)asInhibitorsofHMG-CoAreductaseThemevalonateanalogsareusedtotreathypercholesterolemiapatients

DevelopmentofStatin5-pyrophosphomevalonateisopentenylpyrophosphategeranylpyrophosphatefarnesylpyrophosphatesqualene2,3-oxidosqualene

HOHOlanosterolcholesterol

19steps

In1976,AkiraEndo,incorporationof[14C]acetateintononsaponifiablelipids,searchedforinhibitorsamongthousandsoffungiculturebroths.

the2008AlbertLasker~DeBakeyClinicalMedicalResearchAwardThescientistswhodevelopedStatinsLipidsaretransportedasvariouslipoproteinparticlesinvertebrateplasmaAnLDLparticleLipoproteinswereclassifiedaccordingtotherelativeamountsoflipidandproteininthecomplex(themoreproteinandlesslipidthedenserthecomplex).Lipoproteins:GoodvsBadcholesterolChylomicrons(synthesizedintheintestine):transportmostlytriacylglycerolsfromintestinetoothertissues;VLDL(synthesizedinliver):releasedintobloodstream,itisconvertedtoIDLandLDLbylipases;LDL(fromVLDLorsynthesizedinliver,badcholesterol):majorcirculatorycomplexfortransportofcholesterolandcholesterolestersfromlivertoothertissues;HDL(synthesizedinliver,goodcholesterol):newlyformedHDLcontainnocholesterolesters,anditfunctionsto

returncholesterolanditsesterstotheliver.

Receptor-mediatedendocytosisofLDL

ElectronmicrographshowingLDL(conjugatedtoferritinforvisualization,darkspots)boundtoacoated-pitregiononthesurfaceofaculturedhumanfibroblastcell.Micrographshowingthisregioninvaginatingandfusingtoformanendocyticvesicle[FromR.G.W.Anderson,M.S.Brown,andJ.L.Goldstein.Cell10(1977):351.]EndocytosisofLDLBoundtoItsReceptorApolipoproteinB-100onthesurfaceofanLDLparticlebindstoLDLreceptorontheplasmamembraneofnonhepaticcells.TheLDLreceptorarelocalizedincoatedpits,whichcontainaspecializedproteincalledclathrin.

Thereceptor-LDLcomplexisinternalizedbyendocytosiswhichbringsthecomplexintoendosome.Endosomesfusewithlysosome,releasingcholesterolandfattyacid.TheproteincomponentoftheLDLparticleishydrolyzedtofreeaminoacids,buttheLDLreceptorisrecycledbacktotheplasmamembrane.Thereleasedunesterifiedcholesterolcanthenbeusedformembranebiosynthesis.Alternatively,itcanbereesterified(acylCoA:cholesterolacyltransferase)forstorageinsidethecell.

Receptor-mediatedendocytosisofLDL

HumanLDLreceptorTherearedifferentdefectsinLDLreceptorthatleadtothesameoverallphenotype:LDLreceptornotmadeLDLreceptorunabletobindLDL(mutationsinN-terminalregion)MutationsinC-terminalregion,whichpreventstheformationofLDL-receptorcomplex.atheroscleroticplaquesDefectiveLDLreceptorsre