111生物化學(xué)理論課件@中科大16氨基酸代謝2009

氨基酸代謝11/26/202311.5AminoAcidMetabolism

Glutamatemetabolism

Alanineandaspartatemetabolism

Glycine,serineandthreoninemetabolism

Methioninemetabolism

Cysteinemetabolism

Valine,leucineandisoleucinedegradation

Valine,leucineandisoleucinebiosynthesis

Lysinebiosynthesis

Lysinedegradation

Arginineandprolinemetabolism

Histidinemetabolism

Tyrosinemetabolism

Phenylalaninemetabolism

Tryptophanmetabolism

Phenylalanine,tyrosineandtryptophanbiosynthesis

Ureacycleandmetabolismofaminogroups

1.6MetabolismofOtherAminoAcids

beta-Alaninemetabolism

Taurineandhypotaurinemetabolism

Aminophosphonatemetabolism

Selenoaminoacidmetabolism

Cyanoaminoacidmetabolism

D-GlutamineandD-glutamatemetabolism

D-ArginineandD-ornithinemetabolism

D-Alaninemetabolism

Glutathionemetabolism

http://www.genome.jp/kegg/pathway.html11/26/2023211/26/202331,Proteincatabolism2,Theaminogroupcatabolism3,NitrogenExcretionandtheUreaCycle4,Catabolicpathwaysofaminoacids5,Nitrogencycleandfixation6,Synthesispathwaysofaminoacids7,Aminoacidderivates11/26/20234Sourceandfatesofaminoacidsinthebody11/26/20235AMINOACIDPOOLProteolysisofdietaryproteinsinthestomachandlumenofthesmallintestinereleasesfreeaminoacidsintothebloodstream.Proteolysisofproteinsthatmovethroughtheendocyticpathwaytakesplaceinthelysosomesofallcells.Controlled

proteolysisofubiquitin-taggedintracellularproteinstakesplaceintheproteasomesofallcells.11/26/20236LysosomalDegradation1.Lysosomesdegradeproteinstakenupbyendocytosis,orproteinsthattrafficwithintheendocyticpathway.2.Lysosomescontain~50hydrolyticenzymes(proteases).TheirpHoptimaisacidic,~5.3.Inwell-nourishedcells,lysosomalproteindegradationisnon-selective.4.Instarvingcells,thereisaselectivepathwaythatpreferentiallydegradescytosolicproteinscontainingthepentapeptideKFERQ(Lys-Phe-Glu-Arg-Gln).11/26/20237ControlledProteolysis1.Ubiquitintagsproteinsfordestruction.2.Theproteasomedigeststheubiquitintaggedproteins.3.Proteindegradationcanbeusedtoregulatebiologicalfunction.11/26/20238Ubiquitin

(76Res.)

C-terminalGlyattachestotheε-aminogroupsofseveralLysonaproteindestinedfordegradation.

AdditionalubiquitinmoleculescanbeaddedtoLys48.TheMarkofDeath11/26/20239UbiquitinConjugationE1=Ubiquitin-ActivatingEnzymeE2=Ubiquitin-ConjugatingEnzymeE3=Ubiquitin-ProteinLigase11/26/202310Ubiquitinattachedtothee-aminogroupoflysineresiduesonthetargetproteins11/26/202311Asingleubiquitinmoleculeisapoorsignalfordegradation.Chainsof4ormoreubiquitinmoleculesareverystrongsignalfordegradation.11/26/202312Whatdetermineswhetheraproteinisubiquitinated?ThesubstratespecificityofeachE3.1.TheN-terminalrule:thechemicalnatureoftheamino-terminalaminoacid.2.Cyclindestructiveboxes:specificaminoacidsequencesthatmarkcell-cycleproteinsfordestruction.3.PESTsequences:proteinsrichinproline,glutamicacid,serineandthreonine.ψKXE,whereψisanaliphatic(脂肪族)

residue11/26/202313The26Sproteasomedigeststheubiquitintaggedproteins19Sregulatorysubunit20Sproteasome(catalyticactivity)19Sregulatorysubunit11/26/202314The20SProteasome1.700kD,28homologoussubunits:14oftypeaand14oftypeb.2.Subunitsarearrangedin4ringsof7subunitseachtoformasealedbarrel.

777711/26/2023157777ProteolyticactivityresidesintheN-terminalthreonineresiduesofthebsubunits11/26/202316Accesstothe20Sproteasomeiscontrolledbythe19SCapsThe19Sregulatorysubunitsbindtopolyubiquitinchains.11/26/20231711/26/2023181,Proteincatabolism2,Theaminogroupcatabolism3,NitrogenExcretionandtheUreaCycle4,Catabolicpathwaysofaminoacids5,Nitrogencycleandfixation6,Synthesispathwaysofaminoacids7,Aminoacidderivates11/26/202319Inanimals,aminoacidsundergooxidativedegradationinthreedifferentmetaboliccircumstances:Duringthenormalsynthesisanddegradationofcellularproteins,someaminoacidsthatarereleasedfromproteinbreakdownandarenotneededfornewproteinsynthesisundergooxidativedegradation.2.Whenadietisrichinproteinandtheingestedaminoacidsexceedthebody’sneedsforproteinsynthesis,thesurplusiscatabolized;aminoacidscannotbestored.3.Duringstarvationorinuncontrolleddiabetesmellitus,whencarbohydratesareeitherunavailableornotproperlyutilized,cellularproteinsareusedasfuel.11/26/20232011/26/202321DisposalofAminoGroups(1):TransaminationReactionsGenerallythefirststepofaminoaciddegradationTransferofaminogroupfrommanyaminoacidstolimitednumberofketoacidacceptorsPyruvate(丙酮酸)——>alanineOxaloacetate(草酰乙酸)——>aspartate-a-keto-glutarate(a-酮戊二酸)——>glutamate11/26/202322DisposalofAminoGroups(2):DeaminationReactionsGlutamatedehydrogenaseoxidativedeamination（氧化脫氨）ImportantinliverwhereitreleasesammoniaforureasynthesisHydrolyticdeamination（水解脫氨）Glutaminase&asparaginase11/26/202323DisposalofAminoGroups(3):GlutamineSynthetaseImportantplasmatransportformofnitrogenfrommuscleDetoxificationofammoniaBrainLiver11/26/202324Inmanyaminotransferasereactions,α-ketoglutarateistheaminogroupacceptor.Allaminotransferaseshavepyridoxalphosphate(PLP)ascofactor.Althoughthereactionisshownhereinthedirectionoftransferoftheaminogrouptoα-ketoglutarate,itisreadilyreversible.Enzyme-catalyzedtransaminations.11/26/202325Pyridoxalphosphate(PLP)anditsaminatedform,pyridoxaminephosphatePyridoxalphosphateisboundtotheenzymethroughnoncovalentinteractionsandaSchiffbaselinkagetoaLysresidueattheactivesite.PLP(red)boundtooneofthetwoactivesitesofthedimericenzymeaspartate

aminotransferase,atypicalaminotransferase;close-upviewoftheactivesite,withPLP(red,withyellowphosphorus)inaldiminelinkagewiththesidechainofLys258(purple);anotherclose-upviewoftheactivesite,withPLPlinkedtothesubstrateanalog2-methylaspartate(green)viaaSchiffbase(PDB:1AJS).11/26/202326Reactioncatalyzedbyglutamatedehydrogenase.

TheglutamatedehydrogenaseofmammalianliverhastheunusualcapacitytouseeitherNADorNADPascofactor.Theglutamatedehydrogenasesofplantsandmicroorganismsaregenerallyspecificforoneortheother.ThemammalianenzymeisallostericallyregulatedbyGTPandADP.11/26/202327Ammoniatransportintheformofglutamine.

Excessammoniaintissuesisaddedtoglutamatetoformglutamine,aprocesscatalyzedbyglutaminesynthetase.Aftertransportinthebloodstream,theglutamineenterstheliverandNH4isliberatedinmitochondriabytheenzymeglutaminase.11/26/202328Glucose-alaninecycle.

Alanineservesasacarrierofammoniaandofthecarbonskeletonofpyruvatefromskeletalmuscletoliver.Theammoniaisexcretedandthepyruvateisusedtoproduceglucose,whichisreturnedtothemuscle.11/26/202329SUMMARYMetabolicFatesofAminoGroups■Humansderiveasmallfractionoftheiroxidativeenergyfromthecatabolismofaminoacids.Aminoacidsarederivedfromthenormalbreakdown(recycling)ofcellularproteins,degradationofingestedproteins,andbreakdownofbodyproteinsinlieuofotherfuelsourcesduringstarvationorinuncontrolleddiabetesmellitus.■Proteasesdegradeingestedproteinsinthestomachandsmallintestine.Mostproteasesareinitiallysynthesizedasinactivezymogens.■Anearlystepinthecatabolismofaminoacidsistheseparationoftheaminogroupfromthecarbonskeleton.Inmostcases,theaminogroupistransferredtoα-ketoglutaratetoformglutamate.Thistransaminationreactionrequiresthecoenzymepyridoxalphosphate.■Glutamateistransportedtolivermitochondria,whereglutamatedehydrogenaseliberatestheaminogroupasammoniumion(NH4＋).Ammoniaformedinothertissuesistransportedtotheliverastheamidenitrogenofglutamineor,intransportfromskeletalmuscle,astheaminogroupofalanine.■Thepyruvateproducedbydeaminationofalanineintheliverisconvertedtoglucose,whichistransportedbacktomuscleaspartoftheglucose-alaninecycle.11/26/2023301,Proteincatabolism2,Theaminogroupcatabolism3,NitrogenExcretionandtheUreaCycle4,Catabolicpathwaysofaminoacids5,Nitrogencycleandfixation6,Synthesispathwaysofaminoacids7,Aminoacidderivates11/26/202331Ureacycleandreactionsthatfeedaminogroupsintothecycle.Theureacycleconsistsoffoursteps.1Formationofcitrulline(瓜氨酸)fromornithine(鳥氨酸)andcarbamoyl(氨基甲酰)phosphate(entryofthefirstaminogroup);thecitrullinepassesintothecytosol.2Formationofargininosuccinatethroughacitrullyl-AMPintermediate(entryofthesecondaminogroup).3Formationofargininefromargininosuccinate;thisreactionreleasesfumarate(延胡索酸),whichentersthecitricacidcycle.4Formationofurea;thisreactionalsoregeneratesornithine.11/26/202332Theinterconnectedcycleshavebeencalledthe“Krebsbicycle.”Thepathwayslinkingthecitricacidandureacyclesarecalledtheaspartate-argininosuccinateshunt;theseeffectivelylinkthefatesoftheaminogroupsandthecarbonskeletonsofaminoacids.Theinterconnectionsareevenmoreelaboratethanthearrowssuggest.Linksbetweentheureacycleandcitricacidcycle.Citrulline(瓜氨酸)11/26/202333Ureacycle:locationandsourceofatomsUreasynthesistakesplacemostlyintheliver.OneNatomofureacomesfromAsp(blue).OneNatomcomesfromNH4+(green).OneCatomcomesfromCO2(red).Ornithine(鳥氨酸)actsasacarrierofvariousatomsintheprocessofsynthesizingurea.瓜氨酸鳥氨酸11/26/202334CompartmentalizationoftheureacycleTakesplaceintheliver.Twointracellularlocations:Mitochondrialmatrix:carbamoylphosphateformationandcitrullinesynthesis.Cytosol:argininosuccinateformation;cleavageofargininosuccinatetoarginineandfumarate;hydrolysisofargininetoornithineandurea.瓜氨酸鳥氨酸11/26/202335SUMMARYNitrogenExcretionandtheUreaCycle■Ammoniaishighlytoxictoanimaltissues.Intheureacycle,ornithinecombineswithammonia,intheformofcarbamoylphosphate,toformcitrulline.Asecondaminogroupistransferredtocitrullinefromaspartatetoformarginine—theimmediateprecursorofurea.Arginasecatalyzeshydrolysisofargininetoureaandornithine;thusornithineisregeneratedineachturnofthecycle.■Theureacycleresultsinanetconversionofoxaloacetate(草酰乙酸)tofumarate(延胡索酸),bothofwhichareintermediatesinthecitricacidcycle.Thetwocyclesarethusinterconnected.■Theactivityoftheureacycleisregulatedatthelevelofenzymesynthesisandbyallostericregulationoftheenzymethatcatalyzestheformationofcarbamoylphosphate(氨甲酰磷酸).11/26/2023361,Proteincatabolism2,Theaminogroupcatabolism3,NitrogenExcretionandtheUreaCycle4,Catabolicpathwaysofaminoacids

5,Nitrogencycleandfixation6,Synthesispathwaysofaminoacids7,Aminoacidderivates11/26/202337Summaryofaminoacidcatabolism.11/26/20233811/26/202339ThreonineValine11/26/202340Someenzymecofactorsimportantinone-carbontransferreactions.Thenitrogenatomstowhichone-carbongroupsareattachedintetrahydrofolateareshowninblue.11/26/202341AlaGlyCysSerTrpThr11/26/202342TrpLysPheTyrIle11/26/202343PheTyrHomogentisate(尿黑酸)11/26/202344ArgHisGluGlnPro11/26/202345MetIleThrVal11/26/202346Val,Ile,Leu11/26/202347AsnAsp11/26/202348SUMMARYPathwaysofAminoAcidDegradation■Afterremovaloftheiraminogroups,thecarbonskeletonsofaminoacidsundergooxidationtocompoundsthatcanenterthecitricacidcycleforoxidationtoCO2andH2O.Thereactionsofthesepathwaysrequireanumberofcofactors,includingtetrahydrofolateandS-adenosylmethionineinone-carbontransferreactionsandtetrahydrobiopterinintheoxidationofphenylalaninebyphenylalaninehydroxylase.■Dependingontheirdegradativeendproduct,someaminoacidscanbeconvertedtoketonebodies,sometoglucose,andsometoboth.Thusaminoaciddegradationisintegratedintointermediarymetabolismandcanbecriticaltosurvivalunderconditionsinwhichaminoacidsareasignificantsourceofmetabolicenergy.■Thecarbonskeletonsofaminoacidsenterthecitricacidcyclethroughfiveintermediates:acetyl-CoA,α-ketoglutarate,succinyl-CoA,fumarate,andoxaloacetate.Somearealsodegradedtopyruvate,whichcanbeconvertedtoeitheracetyl-CoAoroxaloacetate.11/26/202349■Theaminoacidsproducingpyruvatearealanine,cysteine,glycine,serine,threonine,andtryptophan.Leucine,lysine,phenylalanine,andtryptophanyieldacetyl-CoAviaacetoacetyl-CoA.Isoleucine,leucine,threonine,andtryptophanalsoformacetyl-CoAdirectly.■Arginine,glutamate,glutamine,histidine,andprolineproduceα-etoglutarate;isoleucine,methionine,threonine,andvalineproducesuccinyl-CoA;fourcarbonatomsofphenylalanineandtyrosinegiverisetofumarate;andasparagineandaspartateproduceoxaloacetate.■Thebranched-chainaminoacids(isoleucine,leucine,andvaline),unliketheotheraminoacids,aredegradedonlyinextrahepatictissues(肝外組織).■Anumberofserioushumandiseasescanbetracedtogeneticdefectsintheenzymesofaminoacidcatabolism.11/26/2023501,Proteincatabolism2,Theaminogroupcatabolism3,NitrogenExcretionandtheUreaCycle4,Catabolicpathwaysofaminoacids5,Nitrogencycleandfixation6,Synthesispathwaysofaminoacids7,Aminoacidderivates11/26/202351Thenitrogencycle.Thetotalamountofnitrogenfixedannuallyinthebiosphereexceeds1011kg.Nitrification(硝化)Denitrification(去硝化)11/26/202352Onlycertainprokaryotescanfixatmosphericnitrogen.Theseincludethecyanobacteria(藍藻類細菌)ofsoilsandfreshandsaltwaters,otherkindsoffree-livingsoilbacteriasuchasAzotobacter(固氮菌)species,andthenitrogen-fixingbacteriathatliveassymbionts(共生體)intherootnodulesofleguminous(豆類)plants.11/26/202353AmmoniaIsIncorporatedintoBiomoleculesthroughGlutamateandGlutamine11/26/20235411/26/20235511/26/20235611/26/2023571,Proteincatabolism2,Theaminogroupcatabolism3,NitrogenExcretionandtheUreaCycle4,Catabolicpathwaysofaminoacids5,Nitrogencycleandfixation6,Synthesispathwaysofaminoacids7,Aminoacidderivates11/26/202358Overviewofaminoacidbiosynthesis.Thecarbonskeletonprecursorsderivefromthreesources:glycolysis,thecitricacidcycle,andthepentosephosphatepathway.11/26/202359Erythrose:赤蘚糖11/26/202360Mostmicroorganismscansynthesizeall20aminoacidsHumanscanonlysynthesize11aminoacidsTheessentialaminoacidscannotbemadebyhumansandmustbeobtainedinthediet.11/26/20236111/26/20236211/26/20236311/26/20236411/26/202365Chorismate:分支酸Phosphoenolpyruvate:磷酸烯醇丙酮酸Erythrose4-phosphate:赤蘚糖-4-磷酸11/26/2023661,Proteincatabolism2,Theaminogroupcatabolism3,NitrogenExcretionandtheUreaCycle4,Catabolicpathwaysofaminoacids5,Nitrogencycleandfixation6,Synthesispathwaysofaminoacids7,Aminoacidderivates11/26/202367Severalaminoacidscanfunctionasneurotransmitterswithoutanychemicalmodification:

Glutamate/Glu/E

Glycine/Gly/G

Aspartate/Asp/D11/26/202368Phosphocreatine,derivedfromcreatine,isanimportantenergybufferinskeletalmuscle.Synthesisofcreatine(肌酸)andcreatinine

(肌酐)11/26/2023691.Itcannonenzymaticallyreducesubstances,suchasperoxidesorfreeradicals,whichaccumulateincellsunderoxidizingconditions.Bymaintaininganintracellularreducingenvironment,glutathionepreventsintracellularproteinthiolsfromoxidizingtodisulfides.2.Inconjunctionwithglutathione

S-transferases(GSTs),glutathioneparticipatesindetoxificationofmanysubstances,suchasorganichalides,fattyacidperoxidesderivedfromlipidoxidation,andproductsderivedfromradiation-damagedDNA.谷胱甘肽11/26/202370神經(jīng)遞質(zhì)腎上腺素去腎上腺素組胺5-羥色胺11/26/202371Spermidine亞精胺andspermine精胺areinvolvedinDNApackaging11/26/202372Nitricoxide,isinvolvedinmanysignalingprocessesinthebody.Forexample,itisasignal-transducingagentinthevasodilation(血管舒張)ofendothelialvascularcells(血管內(nèi)皮細胞)andunderlyingsmoothmuscle.Itisalsoinvolvedinsignalingdecreasesinbloodpressure,andinhibitingplateletaggregation.Intheinflammatoryandimmuneresponses,aninducibleformofnitricoxidesynthaseproducesnitricoxideatlevelssufficienttobetoxictopathogenicorganisms.Finally,itcanactinneurotransmissioninthecentralnervoussystemandstimulateerectionofthepenis.Nitricoxideisagassoitcandiffuserapidlyintoneighboringcellsandcontroltheirmetabolism.Itisalsounstable,withahalf-lifeof1to5seconds,soitseffectsareshort-lived.Inthecell,nitricoxideactsprimarily