核苷酸的代谢（英文版）完整版

MetabolismofNucleotidesLearningoutcomes

Bytheendofthislecture,youshouldlearn:

DemonstrateanunderstandingofthemajorpathwaysofnucleotidemetabolismDescribethebiosynthesisanddegradationofpurine&pyrimidinenucleotide.Understandtheconceptofantimetabolicdrugs，andgraspthemechanismofthesedrugs.NucleosideandNucleotideNitrogenousbaseriboseNitrogenousbaseribosephosphateNucleoside=Nucleotide=PurinesvsPyrimidinesSignificancesofnucleotides1.PrecursorsforDNAandRNAsynthesis2.Essentialcarriersofchemicalenergy,especiallyATP3.ComponentsofthecofactorsNAD+,FAD,andcoenzymeA4.FormationofactivatedintermediatessuchasUDP-glucose,SAMandPAPS.5.cAMPandcGMP,arealsocellularsecondmessengers.NucleoproteinNucleicacidProteinNucleotideNucleosidePhosphateBaseRiboseNucleotidaseNucleosidaseDegradationofnucleicacidInstomachGastricacidandpepsinInsmallintestineNucleases:RNaseandDNaseSection1

BiosynthesisandDegradationofPurineNucleotides

StructureofpurinenucleotideGMPAMPTherearetwopathwaysleadingtonucleotidesDenovosynthesis:Thesynthesisofnucleotidesbeginswiththeirmetabolicprecursors:aminoacids,ribose-5-phosphate,CO2,andone-carbonunits.Salvagepathways:Thesynthesisofnucleotidebyrecyclethefreebasesornucleosidesreleasedfromnucleicacidbreakdown.§1.1DenovosynthesisSite:incytosolofliver,smallintestineandthymusCharacteristics:

a.Purinesaresynthesizedusing5-phosphoribose(R-5-P)asthestartingmaterialstepbystep.

b.

PRPP(5-phosphoribosyl-1-pyrophosphate)isactivedonorofR-5-P.

c.

AMPandGMParesynthesizedfurtheratthebaseofIMP(Inosine-5'-Monophosphate).N10-FormyltetrahydrofolateN10-Formyltetrahydrofolate1.ElementsourcesofpurinebasesFirst,synthesisInosine-5'-Monophosphate,IMP2.SynthesisofInosineMonophosphate(IMP)BasicpathwayforbiosynthesisofpurineribonucleotidesStartsfromribose-5-phosphate(R-5-P)Requires11stepsoveralloccursprimarilyintheliver3.ConversionofIMPtoAMPandGMPNote:GTPisusedforAMPsynthesis.Note:ATPisusedforGMPsynthesis.IMPistheprecursorforbothAMPandGMP.4.FormationofNDPandNTP

AMP+ATP

2ADP

NDP+ATP

NTP+ADPAdenylatekinasenucleosidediphosphatekinase§1.2SalvagepathwayPurinebasescreatedbydegradationofRNAorDNAandintermediateofpurinesynthesiscanbedirectlyconvertedtothecorrespondingnucleotides.PurineNucleosideThesignificanceofsalvagepathway:

a.Savethefuel.

b.Sometissuesandorganssuchasbrainandbonemarrowareonlycapableofsynthesizingnucleotidesbyasalvagepathway.Thecourseofsalvagepathway:

HGPRT:Hypoxanthine-guaninephosphoribosyltransferaseAPRT:AdeninephosphoribosyltransferaseAbsenceofactivityofHGPRTleadstoLesch-Nyhansyndrome.Lesch-Nyhansyndrome§1.3Exchangebetweenpurines§1.4FormationofdeoxyribonucleotideFormationofdeoxyribonucleotideinvolvesthereductionofthesugarmoietyofribonucleosidediphosphates(ADP,GDP,CDPorUDP).Deoxyribonucleotidesynthesisatthenucleosidediphosphate(NDP)level.

DeoxyribonucleotidesynthesisattheNDPlevel§1.5Antimetabolitesofpurinenucleotides

Antimetabolitesofpurinenucleotidesarestructuralanalogsofpurine,aminoacidsandfolicacid.Theycaninterfere,inhibitorblock

synthesispathwayofpurinenucleotidesandfurtherblocksynthesisofRNA,DNA,andproteins.1.Purineanalogs6-Mercaptopurine(6-MP)isaanalogofhypoxanthine.2.AminoacidanalogsAzaserine(AS)isaanalogofGln.3.FolicacidanalogsAminopterin

(AP)

and

Methotrexate(MTX)§1.6DegradationofPurineNucleotidesTheuricacidandthegoutUricacid

Over8mg/dl,intheplasmaGout,Uratecrystallization

injoints,softtissue,cartilageandkidneyHypoxanthineXanthineOutofbodyInurineDiabetesenephrosis……AdvancedGout

ClinicallyApparentTophi11.PhotoscourtesyofBrianMandell,MD,PhD,ClevelandClinic.2.PhotocourtesyofN.LawrenceEdwards,MD,UniversityofFlorida.3.ACRClinicalSlideCollectionontheRheumaticDiseases,1998.213Allopurinol（别嘌呤醇）

–asuicideinhibitorusedtotreatGoutXanthineoxidaseXanthineoxidaseSection2

SynthesisandDegradationofPyrimidineNucleotidesstructureofpyrimidinenucleotideshorterpathwaythanforpurinesPyrimidineringismadefirst,thenattachedtoribose-P(unlikepurinebiosynthesis)only2precursors(aspartateandglutamine,plusHCO3-)contributetothe6-memberedringrequires6steps(insteadof11forpurine)theproductisUMP(uridinemonophosphate)§2.1Denovosynthesis1.Elementsourceofpyrimidinebase2.SynthesisofUMPEnzyme：carbamoylphosphatesynthetaseⅡ（CPS-Ⅱ）

CPSⅠ

CPSⅡ

location

Mit（liver)

Cytosol(allthecell)

sourceofnitrogen

NH3

Gln

allostericagent

AGA

none

function

ureasynthesis

pyrimidinebiosynthesis

DifferenceofcarbamoylphosphatesynthetaseⅠandⅡ3.UTPandCTPbiosynthesisUDPADPUTPATPADPUMPATPkinasekinaseAmidationatthenucleosidetriphosphatelevel.4.FormationofdTMPTheimmediateprecursorofthymidylate(dTMP)isdUMP.TheformationofdUMPeitherbydeaminationofdCMPorbyhydrolyzationofdUDP.Theformeristhemainroute.dTMPdTDPdTTPdUMPdUDPdCMPdCDPN5,N10-methylene-tetrahydrofolicAcidATPATPADPADPdTMPsynthetase

UDPdTMPsynthesisatthenucleosidemonophosphatelevel.§2.2Salvagepathway§2.3Antimetabolitesofpyrimidinenucleotides

Anti