尿素循环英文版生物化学

尿素循环英文版生物化学尿素循环英文版生物化学尿素循环英文版生物化学尿素循环英文版生物化学尿素循环英文版生物化学尿素循环英文版生1尿素循环英文版生物化学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:陆地的;reptile:爬行动物threewaysofAmmoniaexcretionammonotelic:排氨的;uricotelic:排尿酸的;ureotelic:排尿素的2024/4/36Manyaquaticanimals:areammoSourcesandfatesofammoniainthebodySourcesofammonia⑴yieldedbydeaminationofaminoacids;⑵absorbedfromintestinalduct;⑶secretedbyepitheliaofrenaltube(肾小管).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(呕吐)periodically.Ifleftuntreated,coma(昏迷)andirreversiblebraindamagewillfollow.2024/4/333ThemostcommoncauseofsuchThereasonsforthisarenotentirelyclearbutmaybebecausetheexcessammonialeadstotheincreasedformationofglutamateandglutamine.2024/4/334Thereasonsforthis2024/4/23TAC↓α-glutarateglutamateglutamineNH3NH3

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

resultindepletion(损耗，耗尽)ofthecitricacidcycleintermediateα-ketoglutaratewhichmaythencompromise(损害)energyproduction,especiallyinthebrain.Italsoleadstoanincreaseintheacidicaminoacidsglutamateandglutamine

whichmaydirectlycausedamagetothebrain.hydrocephalus(脑水肿)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