上海交大 生物化学 课件 chapter 29.ppt

CHAPTER29BIOSYNTHESISOFNUCLEOTIDES,Nucleotidesplaykeyrolesinthefollowingbiochemicalprocesses:AsactivatedprecursorsofDNAandRNA核酸前体Theirderivativesareactivatedintermediatesinmanybiosyntheses,e.g.UDP-GlcandCDP-DAGandS-AMet活性中间物ATPisauniversalcurrencyofenergyinbiologicalsystems,GTPpowersmanymovementsofmacromolecules能量通用形式Adeninenucleotidesarecomponentsof3majorcoenzymes:NAD+,FAD,andCoA辅酶Asmetabolicregulators,e.g.cAMPandATP代谢调节物,Nucleotidesaresynthesizedfromsimplebuildingblocks(denovosynthesis从头合成)orbytherecyclingofpreformedbases(salvagesynthesis节约利用途经)Purines(Pur.)andpyrimidines(Pyr.)arebuiltdenovofromAA,FH4derivatives,NH4+andCO2ThePRmoietyofribonucleotidescomesfromPRPP,anactivateddonorDeoxyribonucleotidesaresynthesizedbyreductionofribonucleotides(dNDPfromNDP)Finally,dTMPisformedbymethylation甲基化ofdUMP(UMPdUMPdTMP)Nucleotideanalogsarevaluabledrugsinthetreatmentofcancers(P753),viralinfections,autoimmunediseases,andgeneticdisorderssuchasgout痛风症(P757),ThepurineringissynthesizedfromAA,FH4derivatives,andCO2,ThePurRingisassembleddenovofromseveralsimpleprecursors1.Gly(C-4,C-5,N-7)2.Asp(N-1)3.Gln(N-3,N-9)两次FH4(C-2,C-8)两次CO2(C-6),PRPPisthedonorofthePRunitofnucleotides(Nt),PRPPprovidesPRportionforthesynthesisofPurandPyrNt,justasforthatofTrp,PRPPissynthesizedfromATPandR-5-P,whichisprimarilyformedbyPPPPRPPsynthetasecatalyzesthetransferofthe-pyrophosphorylgroupofATPtoC-1ofR-5-PPRPPhasan-configurationatC-1,theactivatedcarbonatom-构型,ThePurringisassembledonPR,ThecommittedstepinthedenovosynthesisofPurNtistheformationof5-phosphoribosylamine(5-磷酸核糖胺)fromPRPPandGlncatalyzedbyamido-phosphoribosyltransferase酰胺磷酸核糖转移酶Theamidegroup(酰胺基)fromGlndisplacesthePPigroupattachedtoC-1ofPRPPTheconfigurationatC-1isinvertedfromtointhisreactionTheresultingC-NglycosidicbondhasconfigurationthatischaracteristicofnaturallyoccurringNt-构型是天然存在的核苷酸中的糖苷键的构型ThisreactionisdrivenforwardbythehydrolysisofPPi,PRPPphosphoribosylamine磷酸核糖胺glycinamideribonucleotide甘氨酰胺核苷酸formylglycinamideribonucleotide甲酰甘氨酰胺核苷酸formylglycinamidineribonucleotide甲酰甘氨脒核苷酸5-aminoimidazoleribonucleotide5-氨基咪唑核苷酸1N2C2N3C2N3C3N成环(3C2N+侧链1N)胺基1N+Gly2C1N+甲酰基1C+胺基1N咪唑环3C2N+侧1N5-aminoimidazole-4-carboxylateribonucleotide5-氨基咪唑4-羧酸核苷酸5-aminoimidazole-4-N-succinocarboxamideribonucleotide5-氨基咪唑4-N-琥珀酸氨甲酰核苷酸5-aminoimidazole-4-carboxamideribonucleotide5-氨基咪唑4-氨甲酰核苷酸5-formamidoimidazole-4-carboxamideribonucleotide5-甲酰胺咪唑-4-氨甲酰核苷酸IMP次黄苷酸(3C2N+)1N1C1N5C2N1C2N2C2N成环(5C4N)侧链氨基1N+CO21C+Asp4C1N延胡索酸4C+甲酰基1C次黄嘌呤5C4N,AMPandGMPareformedfromIMP,IMP,theproductofthedenovopathway,istheprecursorofAMPandGMPIMPadenylosuccinate腺苷琥珀酸AMPThedifferencebetweenAMPandIMPisthesubstitutionofanNH2forthe=OatC-6IMPXMP黄苷酸GMP,IntheconversionsofIMPintoAMPandGMP,acarbonyl(羰基)oxygenatomisreplacedbyanaminogroupsimilarly,inthesynthesisofIMPstep4;intheformationofCTPfromUTP(P748);andintheconversionofCitintoArgintheureacycle(P635)Thecommonmechanisticthemeofthesereactionsistheconversionofthecarbonyloxygenintoaderivativethatcanbereadilydisplacedbyanaminogroup羰基氧(含有磷酸基的衍生物)氨基,ThereactionmechanismforreplacementofacarbonyloxygenbyanaminogroupisshownbyFig29-8TheattackingnitrogencanbefromNH3,GlnorAsp(三者都有氨基),TheleavinggroupinthisclassofreactionscanbePi,PPiortheAMP(三者都有磷酸基)moiety,Purbasescanberecycledbysalvage补救reactionsthatutilizePRPP,PurNt(嘌呤核苷酸)canbesynthesizedfromthepreformedbases(formedfromthehydrolyticdegradationofNAandNt)byasalvagereaction节约利用途经(反应),whichissimplerandmuchlesscostlythanthereactionsofthedenovopathwayInthesalvagereactions补救途经(节约利用途经),thePRmoietyofPRPPistransferredtoaPurtoformthecorrespondingNtTwosalvageenzymeswithdifferentspecificitiesrecoverPurbasesAdeninephosphoribosyltransferase腺嘌呤磷酸核糖转移酶(APRT):Adenine+PRPPAMP+PPiHypoxanthine-guaninephosphoribosyltransferase次黄嘌呤-鸟嘌呤磷酸核糖转移酶(HGPRT):Hypoxanthine(orguanine)+PRPPIMP(orGMP)+PPi.,AMP,GMP,andIMParefeedbackinhibitorsofPurNtbiosynthesis,ThesynthesisofPurNtiscontrolledbyfeedbackinhibitionandotherregulatorymechanismsatseveralsites,5-phosphoribosyl-1-pyrophosphatesynthetase5-磷酸核糖-1-焦磷酸合成酶,theenzymethatsynthesizesPRPP,ispartiallyinhibitedbyPurNtTheenzymeisnottotallyswitchedoffwhenPurareabundantforPRPPisalsoaprecursorofPyrandofHisThecommittedstepinPurNtbiosynthesisistheconversionofPRPPintophosphoribosylamine磷酸核糖胺byGln-PRPPamidotransferase谷酰胺PRPP酰胺基转移酶Thiskeyenzymeisfeedback-inhibitedbymanyPurNtItisnoteworthythatAMPandGMP,thefinalproductsofthepathway,aresynergistic协同的ininhibitingtheamidotransferase,Inosinate(IMP)(次黄苷酸)isthebranchpointinthesynthesisofAMPandGMPThereactionsleadingawayfromIMParesitesoffeedbackinhibitionAMPandGMPinhibittheconversionofIMPintoadenylosuccinate腺苷琥珀酸andIMPintoXMP黄苷酸GTPandATParethesubstratesinthesynthesisofAMPandGMPreciprocally交互ThisreciprocalsubstraterelationtendstobalancethesynthesisofadenineandguanineNt使两种嘌呤核苷酸的合成平衡InE.coli,mostofthegeneencodingenzymesofthedenovopathwayarecoordinatelyregulatedSpecifically,theirtranscriptionisblockedbythepurinerepressor(PurR)嘌呤阻抑蛋白,aDNA-bindingprotein,whenhypoxanthine(次黄嘌呤)andguanineareabundant.嘌呤嘌呤阻抑蛋白与DNA结合阻断转录编码从头合成嘌呤核苷酸的酶,ThePyrringissynthesizedfromcarbamoylphosphate氨甲酰磷酸andAsp,thePyrringisassembledfirstandthenlinkedtoPRtoformaPyrNt,incontrastwiththereactionsequenceinthedenovosynthesisofPurNt嘌呤核苷酸的合成是在磷酸核糖(PR)的基础上合成嘌呤环(碱基);而嘧啶核苷酸的合成则是先合成嘧啶环(碱基),再加入磷酸核糖(PR).TheprecursorsofthePyrringarecarbamoylphosphateandAspTherearetwomajordifferencesinthesynthesisofcarbamoylphosphateusedtosynthesizePyrandtomakeureacompartmentation:(ineukaryotes)inthecytosol(forPyr)andinmito(forurea),respectively,andbydifferentcarbamoylphosphatesynthetase区域不同(合成酶不同),GlnratherthanNH4+istheNdonorinthecytosolicsynthesisofcarbamoylphosphate氮供体不同Also,N-acetylglutamatedoesnotserveasanallostericactivatorinthecytosolicsynthesis.(变构激活剂需否)Gln+2ATP+HCO3carbamoylphosphate+2ADP+Pi+GluThecommittedstepinthebiosynthesisofPyristheformationofN-carbamoylaspartateN-氨甲酰天冬氨酸fromAspandcarbamoylphosphate4C1N+1C1N=5C2N=4C2N(嘧啶环)+1C(侧链羧基,后脱去)Thiscarbamoylation氨甲酰化iscatalyzedbyAsptranscarbamoylase天冬氨酸转氨甲酰酶,ThePyrringisformedinthecarbamoylaspartatecyclization环化withlossofwatertoyielddihydroorotate(DHO,二氢乳清酸,由二氢乳清酸酶催化).Orotate(乳清酸)isthenformedbydehydrogenationofDHO(由二氢乳清酸脱氢酶催化).,OrotateacquiresaPRmoietyfromPRPPtoformaPyrNt,Orotateorotidylate(OMP)(乳清苷酸)UMPacquisitionofaPRgroupfromPRPPtoformaPyrNt,thisreactionisdrivenbythehydrolysisofPPiOMPisdecarboxylatedtoyieldUMP,amajorPyrNt,Pyrbiosynthesisinhigherorganismsiscatalyzedbymultifunctionalenzymes,InE.coli6enzymesthatsynthesizeUMPfromsimpleprecursorsappeartobeunassociatedIneukaryotes,bycontrast,5ofthemareclusteredintwocomplexesOneofthesemultifunctionalenzymeswasdiscoveredwhenculturedmammaliancellsweretreatedwithN-(phosphonacetyl)-L-Asp(PALA,N-磷酸乙酰-L-天冬氨酸)用抑制剂处理培养的哺乳细胞,发现(在克服抑制作用而继续存活的细胞中)三种酶(Carbamoylphosphatesynthetase,Asptranscarbamoylase,andDHOase)的浓度都(同时)提高了100倍Carbamoylphosphatesynthetase,Asptranscarbamoylase,andDHOasearecovalentlyjoinedinasingle240-kdpolypeptidechainThismultifunctionalenzymeiscalledCADOrotate乳清酸PRtransferaseandOMPdecarboxylasearealsoassociatedineukaryotesMultifunctionalenzymesalsomediatethesynthesisofPurinvertebrates(step2+3+5;6+7;9+10),Indeed,thecovalentlinkageoffunctionallyrelatedenzymesoccursoftenineukaryotes真核生物中功能相关的酶经常共价连接在一起(在同一条多肽链上)ThemammalianFAsynthase,whichcontains7enzymaticactivitiesineachoftwochains,isanotherstrikingexampleTheclusteringofenzymescatalyzingareactionsequencehasseveralpotentialadvantagestheirsynthesisiscoordinatedandtheirassemblyintoacoherentcomplexiseasilyassured协调合成sidereactionsareminimizedassubstratesarechanneledfromonecatalyticsitetothenext副作用少acovalentlylinkedmultifunctionalcomplexislikelytobemorestablethanoneformedbynoncovalentinteractions稳定Multifunctionalenzymesprobablyevolvedbyexonshuffling外显子改组,Nucleoside(Ns)mono-,di-,andtriphosphatesareinterconvertible,TheactiveformsofNtinbiosynthesisandenergyconversionsareNDPandNTPconversionofNMPtoNDPiscatalyzedbyspecificnucleosidemonophosphatekinase核苷单磷酸激酶(12)thatutilizeATPasthephosphoryldonore.g:UMP+ATPUDP+ADP;AMP+ATP2ADP,Nsdiphosphatesandtriphosphatesareinterconvertedbynucleosidediphosphatekinase核苷二磷酸激酶,anenzymethathasbroadspecificity(23)XDP+YTPXTP+YDPXandYcanbeanyofseveralribonucleosidesordeoxyribonucleosides,CTPisformedbyaminationanofUTP,bothCTPandUTParethemajorPyrribonucleotidesTheonlydifference:carbonyloxygenatC-4(UTP)isreplacedbyanaminogroup(CTP),Inmammals,amidegroupofGlnisaminodonor,whereasinE.coliNH4+isusedinthisreactionMammalsavoidshavingahighlevelofNH4+inplasmabygeneratingitinsitu原位fromadonorsuchasGlnATPisconsumedinbothaminationreactionsAsintheconversionsofIMPtoAMPandGMP,anacylphosphateintermediate酰基磷酸中间物isnucleophilically亲核attackedbyanitrogenatom,PyrNtbiosynthesisinbacteriaisregulatedbyfeedbackinhibition,ThecommittedstepinPyrNtbiosynthesisinE.coliistheformationofN-carbamoylaspartatefromAspandcarbamoylphosphateAspartatetranscarbamoylase(ATCase),theenzymethatcatalyzesthisreactionisfeedback-inhibitedbyCTP,thefinalproductinthepathwayAsecondcontrolsiteiscarbamoylphosphatesynthetase,whichisfeedback-inhibitedbyUMP,Ribonucleotidereductase核苷酸还原酶,aradical自由基enzyme,catalyzesthesynthesisofdeoxyribonucleotides脱氧核苷酸,dNtaretheprecursorsofDNA,thatareformedbythereductionofribonucleotidesThe2-hydroxylgroupontheribosemoietyisreplacedbyahydrogenatom,substratesareribonucleosidediphosphatesortriphosphates(NDPorNTP),andultimatereductantisNADPH:NDPdNDPTheelectronsfromNADPHaretransferredtothesubstratethroughaseriesofcarriers:aflavin黄素thesulfhydryls巯基ofasmallproteinapairofironsthatgenerateatyrosylradicalandthenanotherpairofsulfhydrylsRibonucleotidereductasecatalyzesthefinalstage:,Thesubstratespecificityandcatalyticactivityofribonucleotidereductasearepreciselycontrolled,Therearetwoallostericsitesinribonucleotidereductase:oneforoverallactivity(1),anotherforsubstratespecificity(2,3,4)1.NDPdNDPATP+,dATP(overallcatalyticactivity)核糖核苷酸促进,脱氧核糖核苷酸抑制(脱氧核糖核苷酸的形成),以保持核糖核苷酸和脱氧核糖核苷酸之间的平衡2.UDP(CDP)dUDP(dCDP)dATPorATP+(thebalancebetweenPyandPu)嘌呤核苷酸(或脱氧嘌呤核糖核苷酸)促进脱氧嘧啶核糖核苷酸合成3.GDPdGDPdTTP+(thebalancebetweenPyandPu)脱氧嘧啶核糖核苷酸促进脱氧嘌呤核糖核苷酸合成4.ADPdADPdGTP+(thebalancebetweentwodifferentPuNt)鸟嘌呤脱氧核糖核苷酸促进腺嘌呤脱氧核糖核苷酸合成,Thioredoxin硫氧还蛋白andglutaredoxin谷氧还蛋白carryelectronstoribonucleotidereductase(RR),TwocarriersofreducingpowertoribonucleotidereductasewerefoundthioredoxinandglutaredoxinTheprocessofthetransferofthereducingpower(NADPH还原力RR核糖核苷酸还原酶riboseunit底物)isshown:NADPHTR(FAD+TR)硫氧还蛋白还原酶T硫氧还蛋白RRriboseunitNADPHGR(GR+FAD)谷氧还蛋白还原酶G谷胱甘肽GX谷氧还蛋白RRriboseunit,Deoxythymidylate(dTMP)isformedbymethylation甲基化ofdeoxyuridylate(dUMP),uracilisnotacomponentofDNARather,DNAcontainsthymine,themethylatedanalogofuracilthymidylatesynthase胸苷酸合酶catalyzesthisfinishingtouch:dUMPismethylatedtodTMP,ThemethyldonorinthisreactionisaFH4derivative(N5,N10-methyleneFH4)ratherthanS-AMetThemethylgroupinsertedintodTMPismorereducedthanthemethylenegroupinthedonorWhatisthesourceofelectronsforthisreduction?Thetwoelectronscomeintheformofahydrideion(H)fromtheFH4moietyitselfThishydrogenbecomespartofthemethylgroupofdTMPInthisreaction,FH4isoxidizedtoFH2.ThusN5,N10-methyleneFH4servesbothasanelectrondonorandasaone-carbondonorinthemethylationreaction既作为电子供体,又作为一碳单位供体Weseehere,asinthesynthesisofPu,thekeyroleofFH4derivatives.Indeed,NtmetabolismandAAmetabolismarecloselytiedbyone-carbontransfer核苷酸代谢和AA代谢通过一碳单位转移而密切连接,Three-dimensionalstructureofE.colidihydrofolatereductasewithaboundmethotrexate.,ItisnoteworthythatthedeoxyriboseandthymineunitsofDNAareformedbymodificationofribonucleotidesDNA中的脱氧核糖和胸腺嘧啶由RNA中的核糖核苷酸修饰后形成Incontrast,noknownribonucleotideisformedfromadeoxyribonucleotideTheseprecursor-productrelationsstronglyimplythatribonucleotidescamefirstinevolutionThereactionscatalyzedbyribonucleotidereductaseandthymidylatesynthasearerecapitulations(重述)ofthetransitionfromaRNAworldtooneinwhichDNAbecamethestoreofgeneticinformation,Potentcompetitiveinhibitorsofdihydrofolatereductase,(A)Theanticancerdrugsaminopterin氨基蝶呤(4-氨基叶酸)andmethotrexate氨甲蝶呤containanNH2groupinplaceoftheOHgroupofdihydrofolate.MethotrexatealsodiffersinhavingaCH3groupinsteadofHatN10.,(B)Trimethoprim三甲氧苄二氨嘧啶,anantibacterialfolateanalog.,FH2reductasecatalyzestheregenerationofFH4,aone-carboncarrier,ForcarryingOCU,FH4mustberegeneratedfromFH2thatisproducedinthesynthesisofdTMPThisisaccomplishedbyFH2reductaseusingNADPHasthereductant:FH2+NADPH+H+FH4+NADP+AhydrideionisdirectlytransferredfromnicotinamideringofNADPHtopteridineringofFH2,SeveralvaluableanticancerdrugsblockthesynthesisofdTMP,RapidlydividingcellsrequireanabundantsupplyofdTMPforthesynthesisofDNAThevulnerability易受性ofthesecellstotheinhibitionofdTMPsynthesishasbeenexploitedincancerchemotherapydTMPsynthase胸苷酸合酶andFH2reductase二氢叶酸还原酶arechoicetargetenzymesFluorouracil氟尿嘧啶orfluorodeoxyuridine氟脱氧尿苷,achemicallyusefulanticancerdrug,isconvertedinvivointofluorodeoxyuridylate(F-dUMP)ThisanalogofdUMPirreversiblyinhibitsthymidylatesynthaseafteractingasanormalsubstratethroughpartofthecatalyticcycleFirst,asulfhydrylgroupoftheenzymeaddstoC-6oftheboundF-dUMP,-CH2-FH4thenaddstoC-5ofthisintermediateInthecaseofdUMP,ahydrideionofthefolateissubsequentlyshiftedtotheCH2-,andaprotonistakenawayfromC-5oftheboundNtHowever,F+cannotbeabstractedfromF-dUMPbytheenzyme,andsocatalysisisblockedatthestageofthecovalentcomplexformedby(1)F-dUMP,(2)CH2-FH4,and(3)-SHoftheenzymeThisisanexampleofsuicideinhibition自杀抑制,inwhichanenzymeconvertsasubstrateintoareactiveinhibitorthatimmediatelyinactivatesitscatalyticactivityThesynthesisofdTMPcanalsobeblockedbyinhibitingtheregenerationofFH4AnalogsofFH2,suchasaminopterin氨基蝶呤andmethotrexate氨甲蝶呤,arepotentcompetitiveinhibitors(Ki1nmol/L)ofFH2reductase,Methotrexateisavaluabledruginthetreatmentofmanyrapidlygrowingtumors,suchasacuteleukemiaandchoriocarcinoma绒毛膜癌However,itisquitetoxicbecauseitkillsrapidlyreplicatingcellswhethertheyaremalignant恶性ornotStemcellsinbonemarrow骨髓,epithelialcells上皮细胞oftheintestinaltract,andhairfollicles毛囊arevulnerabletotheactionofthisfolateantagonist拮抗剂,accountingformanyofitstoxicsideeffectsFolateanalogssuchastrimethoprim三甲氧苄二氨嘧啶binds105-foldlesstightlytomammalianFH2reductasethanitdoestoreductasesofsusceptiblemicroorganisms,NAD+,FAD,andCoAareformedfromATP,NAD+:nicotinate烟酸,或尼克酸nicotinateNt烟酸核苷酸NicotinateisderivedfromTrp.HumanscansynthesizetherequiredamountofitifthesupplyofTrpinthedietisadequateHowever,anexogenoussupplyofitisrequiredifthedietaryintakeofTrpislow,AdietarydeficiencyofTrpandnicotinatecanleadtopellagra糙皮病,adiseasecharecterizedbydermatitis皮炎,diarrhea腹泻,anddementia痴呆NicotinateNtdesamido-NAD+脱酰胺NAD+NAD+NADP+isderivedfromNAD+byphosphorylationofthe2-hydroxylgroupoftheadenineribosemoietyThistransferofaphosphorylgroupfromATPiscatalyzedbyNAD+kinase,FAD:riboflavin核黄素(VB2)riboflavin5-phosphate(orflavinmononucleotide)flavinadeninedinucleotide黄素腺嘌呤二核苷酸Both5-phosphateandAMPunitcomefromATP,so2ATPconsumedhere,CoA:theAMPmoietyofCoAalsocomesfromATPpantothenate泛酸(+ATP)4-phosphopantothenate4-磷酸泛酸(+Cys+ATP)4-phosphopantothenylcystein4-磷酸泛酰半胱氨酸(CO2)4-phosphopantotheine4-磷酸泛酰巯基乙胺(+ATP)dephospho-CoA脱磷酸CoA(+ATP)CoAAcommonfeatureofthebiosynthesesofNAD+,FAD,andCoAisthetransferoftheAMPmoietyofATPtothephosphategroupofaphosphorylatedintermediateATP将AMP(单位)转移到磷酸化中间物的磷酸基上ThePPiformedinthesecondensationsisthenhydrolyzedtoPiAsinmanyotherbiosyntheses,muchofthethermodynamicdrivingforcecomesfromthehydrolysisofthereleasedPPi,Puinhumansaredegradedtourate尿酸,TheNtofacellundergocontinuousturnoverNtarehydrolyticallydegradedtoNsbynucleotidase核苷酸酶PhosphorylyticcleavageofNstofreebasesandR-1-P(ordeoxyribose1-P)iscatalyzedbyNsphosphorylases核苷磷酸化酶R-1-Pisisomerizedbyphosphoribomutase磷酸核糖变位酶toR-5-P,asubstrateinthesynthesisofPRPPSomeofthebasesarereusedtoformNtbysalvagepathways,AMPIMP(脱氨，腺苷酸脱氨酶）hypoxanthine次黄嘌呤（水解除去磷酸，磷酸解切出核糖）xanthine黄嘌呤uricacid尿酸（以上两步都由黄嘌呤氧化酶催化）Inhumans,urateisthefinalproductofPudegradationandisexcretedintheurine,Gout痛风isinducedbyhighserumlevelsofurate尿酸,Hyperuricemia高尿酸血caninducegout,adiseasethataffectsthejointsandkidneysInflammationofthejointsistriggeredbytheprecipitationofsodiumurate尿酸钠crystals,Micrographofsodiumuratecrystals.,GoutisthoughttobeaninheritedmetabolicdiseaseAsmallproportionofpatientswithgouthaveapartialdeficiencyofhypoxanthine-guaninephosphoribosyltransferase(HGPRT),theenzymecatalyzingthesalvagesynthesisofIMPandGMPAdeficiencyofHGPRTleadstoreducedsynthesisofGMPandIMPbythesalvagepathwayTheconsequentincreaseinthelevelofPRPPmarkedlyacceleratesPubiosynthesisbythedenovopathwayTheformationof5-phosphoribosyl-1-amine,thefirstcommittedintermediate,isnormallylimitedbytheavailabilityofPRPPExcessivePRPPalsointerfereswithfeedbackinhibitionoftheamidotransferase转酰胺酶thatcatalyzesthisstepHGPRT部分缺陷节约利用途径受阻PRPP增加(变构调控受损的高活性PRPP合成酶也导致PRPP增加)嘌呤从头合成加速(限速酶活性升高)嘌呤分解产物(尿酸)增多痛风症GoutcanalsoresultfromexcessPRPPproducedbyahyperactivesynthetase高活性PRPP合成酶havingimpairedallostericregulation,Allopurinol别嘌呤醇,ananalogofhypoxanthineisextensivelyusedtotreatgoutItsmechanismofactionisthatitactsfirstasasubstrateandthenasaninhibitorofxanthineoxidase先作为黄嘌呤氧化酶的底物,(经催化改变)后作为此酶的“自杀”性抑制剂Theoxidasehydroxylatesittoalloxanthine别黄嘌呤,whichthenremainstightlyboundtotheactivesiteThemolybdenum钼atomofxanthineoxidaseiskeptinthe+4oxidationstatebythebindingofalloxanthineinsteadofreturningtothe+6oxidationstateasinanormalcatalyticcycle,Weseehereanotherexampleofsuicideinhibition.(anotherexample:5-FuorF-dUMP)自杀性抑制(原本不具抑制作用的底物经酶的催化作用后与酶共价结合并使之立即失活,即酶自杀“.别嘌呤醇黄嘌呤氧化酶;5-Fu胸苷酸合酶)Thesynthesisofuratefromhypoxanthineandxanthinedecreasessoonaftertheadministrationofallopurinol.Hence,theserumconcentrationofhypoxanthineandxanthinerise,whereasthatofuratedrops血清中次黄嘌呤(和黄嘌呤)浓度升高,而尿酸浓度降低,Theformationofuricacidstonesisvirtuallyabolishedbyallopurinol,andthearthritisbecomeslesssevere.Also,therateofPubiosynthesisdecreasesbecauseallopurinolsequesters螯合PRPPbyformingtheNtFurthermore,allopurinolribonucleotideinhibitstheconversionofPRPPintophosphoribosylamine别嘌呤醇抑制黄嘌呤氧化酶(减少尿酸的生成),螯合PRPP(形成核苷酸)从而减少嘌呤的从头合成,此别嘌呤醇核苷酸抑制由PRPP(+Gln)生成5-磷酸核糖胺(限速步骤),Urateplaysabeneficialroleasapotentantioxidant,averageserumlevelofurateinhumansisclosetosolubilitylimitandistenfoldhigherthan