尿素循環(huán)英文版生物化學(xué)尿素循環(huán)英文版生物化學(xué)尿素循環(huán)英文版生物化學(xué)尿素循環(huán)英文版生物化學(xué)尿素循環(huán)英文版生物化學(xué)尿素循環(huán)英文版生1尿素循環(huán)英文版生物化學(xué)2KeyNotes:AmmoniaexcretionSourcesandfatesofammoniainthebodyTheureacycleRegulationLinktothecitricacidcycleHyperammonemiaFormationofcreatinephosphateTheactivatedmethylcycleUricacidM3Theureacycle2024/4/33KeyNotes:M3Theureacycle2AmmoniaexcretionThereisnostorefornitrogen-containingcompounds

asthereisforcarbohydrate(glycogen)orlipids(triacylglycerol).Thusnitrogen

ingestedinexcessofwhatisrequiredbytheorganismhasto

beexcreted.AmmoniaexcretionThereisnos4Theexcessnitrogen:First,convertedintoammonia,Then,excretedfromlivingorganismsinoneofthreeways.excretionoccursinoneofthreewaysthreeways?2024/4/35Theexcessnitrogen:excretionManyaquaticanimals:

areammonotelicsimplyexcretetheammoniaitselfdirectlyintothesurroundingwater.Birds

andterrestrialreptiles:areuricotelicexcretetheammoniaintheformofuricacid,Mostterrestrialvertebrates:are

ureotelicconverttheammoniaintoureabeforeexcretion.Terrestrialanimalsrequirepathwaysfornitrogenexcretionthatminimizetoxicityandwaterloss

aquatic:水生的;terrestrial:陸地的;reptile:爬行動物threewaysofAmmoniaexcretionammonotelic:排氨的;uricotelic:排尿酸的;ureotelic:排尿素的2024/4/36Manyaquaticanimals:areammoSourcesandfatesofammoniainthebodySourcesofammonia⑴yieldedbydeaminationofaminoacids;⑵absorbedfromintestinalduct;⑶secretedbyepitheliaofrenaltube(腎小管).Sourcesofammoniainthebody2024/4/37SourcesandfatesofammoniaiFatesofammonia⑴ornithinecycle:ureasynthesisfordetoxifyingammonia;⑵glutaminesynthesis:thenontoxicformtotransportandstoreammonia;⑶secretedbyepitheliaofrenaltube:facilitateprotontoexcretefromthebodyintheurine;⑷participateinsynthesisofnonessentialaminoacids.Fatesofammoniainthebody2024/4/38FatesofammoniaFatesofammonTheureacycleUreaissynthesizedintheliverbytheureacycle(alsotermedornithinecycle).thensecretedintothebloodstream,andtakenupbythekidneysforexcretionintheurine.Theroleofureacycleistodetoxifyammonia.Theureacycle:thefirstcyclicmetabolicpathwaydiscoveredbyHansKrebsandKurtHenseleitin1932,5yearslater,KrebsdiscoveredtheTCAcycle.in1953,acquiringtheNobelprize2024/4/39TheureacycleUreaissynthesiTheoverallreactionofthepathwayis:NH4++HCO3-+H2O+3ATP+Aspartate↓Urea+2ADP+AMP+2Pi+PPi

+Fumarate(AMP+ATP→2ADP)TheureacycleOneofthenitrogenatomsofureacomesfromammonia,theotheristransferredfromtheaminoacidaspartate,whilethecarbonatomcomesfromCO2.2024/4/310TheoverallreactionofthepaOrnithine:

anonstandardaminoacid,notfoundinproteins,thecarrierofnitrogenandcarbonatomsinurea.Five

enzymaticreactionsareinvolvedintheureacycle,thefirsttwoofwhichtakeplaceinmitochondria,theotherthree

inthecytosol.(Fig.)2024/4/311Ornithine:FiveenzymaticreacAminoAcidOxidationTheProductionofUrea(CPS-I)2024/4/312AminoAcidOxidationTheProducUreacycleandreactionsthatfeedaminogroupsintothecycle.2024/4/313Ureacycleandreactionsthat1.

CarbamoylphosphatesynthetaseI,

whichistechnicallynotamemberoftheureacycle,catalyzesthecondensationandactivationofammonia(fromtheoxidativedeamination)andCO2

(intheformofbicarbonate,HCO3-)toformcarbamoylphosphate.(Fig.)Carbamoyl:氨基甲酰FiveenzymaticreactionsinTheureacycle(CPS-I)2024/4/3141.CarbamoylphosphatesynthetSynthesis

ofN-acetylglutamateanditsactivationofcarbamoylphosphatesynthetaseI.allostericregulation(CPS-I:keyenzyme)2024/4/315SynthesisofN-acetylglutamateNote:ThehydrolysisoftwoATPmoleculesmakesthisreactionessentiallyirreversible.2.Thesecondreactionalsooccursinthemitochondria,andinvolvesthetransferofthecarbamoylgroupfromcarbamoylphosphatetoornithinebyornithinetranscarbamoylase.(Fig.)(ornithinecarbamoyltransferase,OCT)2024/4/316Note:ThehydrolysisoftwoATUreacycleandreactionsthatfeedaminogroupsintothecycle.2024/4/317UreacycleandreactionsthatNote:Thisreactionformsanothernonstandardaminoacid

citrulline

whichthenhastobetransportedoutofthemitochondrionintothecytosolwheretheremainingreactionsofthecycletakeplace.OCT2024/4/318Note:Thisreactionformsanot3.Thecitrullineisthencondensedwithaspartate,thesourceofthesecondnitrogenatominurea,bytheenzymeargininosuccinatesynthetasetoformargininosuccinate.

(Fig.)2024/4/3193.ThecitrullineisthencondNote:ThisreactionisdrivenbythehydrolysisofATPtoAMPandPPi,withsubsequenthydrolysisofthepyrophosphate.Thusbothofthehigh-energybondsinATPareultimatelycleaved.2024/4/320Note:Thisreaction2024/4/2204.Argininosuccinasethenremovesthecarbonskeletonofaspartatefromargininosuccinateintheformoffumarate,leavingthenitrogenatomontheotherproductarginine.(Fig.)2024/4/3214.Argininosuccinase2024/4/22Note:theureacyclealsoproduces

arginine,thisaminoacidisclassifiedasnonessentialinureotelicorganisms.Arginineistheimmediateprecursorofurea.Metabolicintegrationofnitrogenmetabolism.Theureacycle,gluconeogenesis,andthetransaminationofoxaloacetatearelinkedbyfumarateandaspartate.Note:theureacyclealsoprod225.Theureaisthenformedfromargininebytheactionofarginase

withtheregeneration

ofornithine.(Fig.)Theornithine:isthentransportedbackintothemitochondrionreadytobecombinedwithanothermoleculeofcarbamoylphosphate.2024/4/3235.TheureaTheornithine:202Ureacycleandreactionsthatfeedaminogroupsintothecycle.2ATP+HCO3-+NH3→+2ADP+Pi2024/4/324UreacycleandreactionsthatRegulationDuringprolongedstarvation,whenbreakdownofmuscleproteinbeginstosupplymuchoftheorganism’smetabolicenergy,ureaproductionalsoincreasessubstantially.2024/4/325RegulationDuringprolongedstaCarbamoylphosphatesynthetaseI,thefirstenzymeinthepathway,actsasarate-limitingenzyme,andisallostericallyactivatedbyN-acetylglutamate.Allfiveenzymesaresynthesizedathigherratesinstarvinganimals,andinanimalsonvery-high-proteindietsthaninwell-fedanimalseatingprimarilycarbohydratesandfats.Theactivityoftheureacycleisregulatedattwolevels:(level1)2024/4/326CarbamoylphosphatesynthetaseSynthesisofN-acetylglutamateanditsactivationofcarbamoylphosphatesynthetaseI.level1level2AGA2024/4/327SynthesisofN-acetylglutamateThesteady-statelevelsofN-acetylglutamatearedeterminedbytheconcentrationsofglutamateandacetyl-CoA(thesubstratesforN-acetylglutamatesynthase)andarginine(anactivatorofN-acetylglutamatesynthase,andthusanactivatoroftheureacycle).(level2)Note:TheArgininosuccinaseisthelowestofactivityinallfiveenzymes,anotherrate-limitingenzymeafterstartofthecycleregulatesthesynthesisrateofurea2024/4/328Thesteady-statelevelsofN-aLinktothecitricacidcycleThegenerationoffumaratebyargininosuccinaselinkstheureacycletothecitricacidcycle.

FumarateisanintermediateoftheTCAcyclewhichisthenhydratedtomalate,whichinturnisoxidizedtooxaloacetate.2024/4/329LinktothecitricacidcycleTLinksbetweentheureacycleandcitricacidcycle.2024/4/330Linksbetweentheureacycleatransaminationtoaspartate

whichcanthenfeedbackintotheureacycle;condensationwithacetylCoAtoformcitratewhichthencontinuesonroundthecitricacidcycle;conversionintoglucose

viagluconeogenesis;conversionintopyruvate

viaoxidativedecarboxylationofmalate.Oxaloacetatehasseveralpossiblefates:2024/4/331transaminationtoaspartateOxHyperammonemiaTheanswertothisquestionisobvious:whenoneconsiderswhathappensifthereisablockintheureacycleduetoadefectiveenzyme.Hyperammonemia:Ablockinanyoftheureacycleenzymesleadstoanincreaseintheamountofammoniaintheblood.Whydoorganismsneedtodetoxifyammoniainthefirst-place?(Appendex:)2024/4/332HyperammonemiaTheanswertothThemostcommoncauseofsuchablockisageneticdefectthatbecomesapparentsoonafterbirth,whentheafflictedbabybecomeslethargic(昏睡的)andvomits(嘔吐)periodically.Ifleftuntreated,coma(昏迷)andirreversiblebraindamagewillfollow.2024/4/333ThemostcommoncauseofsuchThereasonsforthisarenotentirelyclearbutmaybebecausetheexcessammonialeadstotheincreasedformationofglutamateandglutamine.2024/4/334Thereasonsforthis2024/4/23TAC↓α-glutarateglutamateglutamineNH3NH3

α-glutarateinbrain↓possiblemechanismforammoniapoisoningshortageofenergeproductioninbrain2024/4/335TAC↓α-glutarateglutamateglutaThesereactions

resultindepletion(損耗，耗盡)ofthecitricacidcycleintermediateα-ketoglutaratewhichmaythencompromise(損害)energyproduction,especiallyinthebrain.Italsoleadstoanincreaseintheacidicaminoacidsglutamateandglutamine

whichmaydirectlycausedamagetothebrain.hydrocephalus(腦水腫)2024/4/336ThesereactionsItalsoleadsFormationofcreatinephosphateTheureacycleis:alsothestartingpointforthesynthesisofcreatinephosphate(anotherimportantmetabolite).

Thisphosphagen(磷酸原)providesareservoirofhigh-energyphosphate

inmusclecells

astheenergyreleaseduponitshydrolysisisgreaterthanthatreleaseduponthehydrolysisofATP(

Gforcreatinephosphatehydrolysis=-43.1kJmol-lcomparedwith-30.5kJmol-lforATPhydrolysis).2024/4/337FormationofcreatinephosphatThefirststepintheformationofcreatinephosphateisthecondensationofarginineandglycinetoformguanidinoacetate(胍乙酸).Ornithineisreleasedinthisreactionandcanthenbere-utilizedbytheureacycle.2024/4/338ThefirststepintheformatioTheguanidinoacetate

isthenmethylatedbythemethylgroupdonorS-adenosylmethionine(SAM)toformcreatine,whichisinturnphosphorylated,bycreatinekinasetoformcreatinephosphate.~2024/4/339Theguanidinoacetate~2024/4/2~2024/4/340~2024/4/240TheactivatedmethylcycleS-Adenosylmethionine(SAM)servesasadonorofmethylgroupsinnumerousbiologicalreactions[e.g.intheformationofcreatinephosphateandinthesynthesisofnucleicacids].Itisformedthroughtheactionoftheactivatedmethylcycle(alsotermedmethioninecycle).2024/4/341TheactivatedmethylcycleS-AdhomocysteinemethyltransferasevitaminB122024/4/342homocysteinemethyltransferaseDuringdonationofitsmethylgrouptoanothercompound,S-adenosylmethionineisconvertedintoS-adenosylhomocysteine(同型半胱氨酸).(Fig.)TheactivatedmethylcycleToregenerateS-adenosylmethionine,theadenosylgroupisremovedfromtheS-adenosylhomocysteinetoformhomocysteine.(Fig.)2024/4/343DuringdonationofitsmethylThisisthenmethylatedbytheenzymehomocysteinemethyltransferase,oneofonlytwovitaminB12-containingenzymesfoundineukaryotes,toformmethionine.TheresultingmethionineisthenactivatedtoS-adenosylmethioninewiththereleaseofallthreeofthephosphatesfromATP.(Fig.)(Fig.)2024/4/344ThisisthenmethylatedbytheUricacidUricacidisthemainnitrogenouswasteproductofuricotelicorganisms(reptiles,birdsandinsects),butisalsoformedinureotelicorganismsfromthebreakdownofthepurinebasesfromDNAandRNA.2024/4/345UricacidUricacid2024/4/245Someindividualshaveahighserumlevelofsodiumurate(thepredominant