生化課件老師-2biosynthesis of amino acids and related molecules

Biosynthesisofaminoacidsandrelatedmolecules

氨基酸及其衍生物

的生物合成

ContentsOverviewofnitrogenmetabolismReduction(fixation)ofN2intoammonia(NH3orNH4+)Synthesisofthe20aminoacidsSynthesisofotherbiomoleculesfromaminoacids1.ThenitrogencycleNitrification硝化作用2.Nitrogenisfixedbyenzymesofthenitrogenase(固氮酶)complexNitrogenfixation:ConversionofN2toNH3indiazotrophs(固氮生物)Cyanobacteria(藍(lán)綠藻,photosynthetic)rhizobia(根瘤菌,symbiont共生生物)RhizobiaexistinnodulesofleguminousplantsCyanobacteriaRhizobiaAmmoniaisincorporatedintobiomoleculesthroughglutamateandglutamineFirst,glutaminesynthetase(Gln合成酶)catalyzedthereactionofglutamateandNH4+toyieldglutamine.Glutamateisproducedfromglutamineandα-ketoglutarateinareactioncatalyzedbyglutamatesynthase(Glu合酶).TheamidegroupofGlnisthesourceofnitrogeninthesynthesisofavarietyofcompounds,suchasTrp,His,carbamoylphosphate(氨基甲酰磷酸),glucosamine-6-P,CTP,andAMP.Theaminogroupsofmostotheraminoacidsarederivedfromglutamatethroughtransamination.Glutaminesynthetaseisaprimaryregulatorypointinnitrogenmetabolism

Theenzymehas12identicalsubunits(eachhavinganindependentactivesiteformingtwohexagonalrings)andisregulatedbybothallostericallyandbycovalentmodification.Thebacterial

Glnsynthetasehas12subunitsarrangedastworingsofhexamersActivesitesTyr397(adenylylationsite)Theglutaminesynthetaseisaccumulativelyinhibitedbyatleast8allostericeffectors,mostlyendproductsofglutaminemetabolismRegulationbyallostericeffectorsAspecificTyrresidue(Tyr397)inbacterialglutaminesynthetasecanbereversibleadenylylatedAdenylylatedenzymeismoresensitivetotheallostericinhibitor(變構(gòu)抑制劑).TheadditionandremovaloftheAMPgrouptotheglutaminesynthetasearecatalyzedbyadenylyltransferase(AT,腺苷?；D(zhuǎn)移酶).ActivityofATismodulatedbybindingtoaregulatoryprotein,PII.TheactivityofPII,inturn,isregulatedbytheuridylylation(尿苷酰化)ofaspecificTyrresidue:PII-UMPstimulatesthedeadenylylationactivityofAT,however,theunmodifiedPIIstimulatestheadenylylationactivityofAT.TheadditionandremovalofUMPtoPIIareagaincatalyzedbyasingleprotein,uridylyltransferase(尿苷?；D(zhuǎn)移酶,UT):α-ketoglutarateandATPstimulatetheuridylylation,however,GlnandPistimulatethedeuridylylation.

SeveralclassesofreactionsplayspecialrolesinthebiosyntesisofaminoacidsandnucleotidesTransaminatonreactionsandotherrearrangementspromotedbyenzymescontainingpyridoxalphosphate.Transferofone-carbongroups.TransferofaminogroupsderivedfromtheamidenitrogenofGln.3.BiosythesisofaminoacidsTransferofaminogroupsderivedfromtheamidenitrogenofGlniscatalyzedby

AmidotransferasesTheenzymecontainstwostructuraldomains:onebindingGln,theotherbindingthesecondsubstrate,whichservesasaminogroupacceptor.AconservedCysresidueisbelievedtoactasanucleophile,cleavingtheamidebondandformingacovalentglutamyl-enzymeintermediate.TheNH3producedremainsattheactivesiteandreactswiththesecondsubstratetoformanaminatedproduct.ProposedmechanismforglutamineamidotransferasesProposedmechanismforglutamineamidotransferases

AllaminoacidsarederivedfromIntermediatesinglycolysis,thecitricacidcycle,orthepentosephosphatepathwayNitrogenentersthesepathwaysbywayofGlnandGlu.Thepathwaysforthebiosynthesisofthe20aminoacidscanbecategorizedintosixfamiliesaccordingtothemetabolicprecursorsused.EssentialandnonessentialaminoacidsOverviewofaminoacidsynthesis赤蘚糖

必需——缺乏碳骨架供給氨基酸的生物合成由糖代謝中間產(chǎn)物轉(zhuǎn)化而來蛋白質(zhì)氨基酸非必需氨基酸糖必需氨基酸酮體哺乳動物大多數(shù)微生物和植物可以合成所有類型氨基酸。AminoacidbiosynthesisisunderallostericregulationAllostericregulationofIlesynthesisConcertedinhibitionInconcertedinhibition(協(xié)同抑制),oneenzymeisinhibitedbytwoormoremodulators,witheffectmorethanadditive.Interlockingregulation(連鎖調(diào)節(jié))Enzymemultiplicity(酶的多樣性):Severalisozymesarepresenttocatalyzeacommonstepofreaction:eachisozymerespondstoadifferentallostericmodulator,avoidingtheinhibitionofacommonreactionbyonlyoneendproduct.InterlockingregulatorymechanismsinthebiosynthesisofseveralaminoacidsderivedfromAspinE.coliSequentialfeedbackinhibition4.MoleculesderivedfromaminoacidsAminoacidsareprecursorsofmanyspecializedbiomoleculesGlycineisaprecursorofporphyrinsRadioisotopetracerexperimentsshowedthattheporphyrin(卟啉)ringofthehemegroupsinmammalsaremadefrom8Glyand8succinyl-CoA(Gluinplantsandbacteria).Deficiencyofenzymesinthehemebiosynthesisleadstodiseasescalledporphyrias(卟啉癥)

.Thedegradationofhemeyieldsbilirubin(膽紅素),alineartetrapyrrole(四吡咯)derivative,andthetypicalpigmentsfoundinbile,urine,andfeces,adeficiencyofwhichwillcausejaundice(黃疸).原卟啉HemeFerrochelatase亞鐵螯合酶Fe2+卟膽原(膽紅素）AminoacidsarereqiredforthebiosynthesisofcreatineandglutathioneCreatine(肌酸),the“energybuffer”inskeletalmuscle,isderivedfromGly,Arg,andMet肌酸合成的反應(yīng)過程肌酸和磷酸肌酸是能量儲存、利用的重要化合物肌酸以甘氨酸為骨架，由精氨酸提供脒基，S-腺苷甲硫氨酸供甲基而合成肝是合成肌酸的主要器官在肌酸激酶（CPK）催化下，肌酸轉(zhuǎn)變成磷酸肌酸肌酸和磷酸肌酸代謝終產(chǎn)物是肌酸酐。肌酸(creatine)Synthesisofglutathione(GSH)GSHistheredox（氧化還原作用）bufferincells,cyclingbetweenGSH(reducedform)andGSSG(oxidizedform).Thetripeptideissynthesizedusingspecificenzymes(notribosomes)GSHprobablyhelpsmaintainthesulfhydrylgroups（巰基）ofproteinsinthereducedstatesandtheironofhemeintheferrous(Fe2+)GSHisanimportantcofactorforglutathioneperoxidase,anenzymecontaininganessentialselenocysteine(硒代半胱氨酸)residueintheactivesite,toremovetoxicperoxidesincells.D-aminoacidsarefoundprimarilyinbacteriaServesomespecialfunctionsinthestructureofbacterialcellwallsandpeptideantibiotics.D-aminoacidsarisedirectlyfromtheL-isomersbytheactionofaminoacidracemases(消旋酶),whichhavePLPascofactor.Aminoacidracemizationisuniquelyimportantobacterialmetabolism,andenzymesareprimetargetsforpharmaceuticalagents.PLPfacilitatestransamination,racemization,decarboxylationofaminoacidsAminoacidsareconvertedtobiologicalaminesbydecarboxylationManyimportantneurotransmitters,e.g.,γ-aminobutyrate(GABA),serotonin(5-hydroxytrptamine,or5-HT,5-羥色胺),dopamine,norepinephrine(去甲腎上腺素),epinephrine(腎上腺素)arederivedfromaminoacidsdecarboxylationreaction.在氨基酸脫羧酶的催化，體內(nèi)部分氨基酸可進行脫羧基作用生成相應(yīng)的胺。催化酶：氨基酶脫羧酶（輔酶為磷酸吡哆醛，PLP）意義：生成的胺類物質(zhì)常具有重要的生理功用或藥理作用*胺氧化酶能將胺類物質(zhì)氧化成醛類或酸類物質(zhì)，從而避免胺類在體內(nèi)蓄積。DecarboxylationPLPfacilitatestransamination,racemization,decarboxylationofaminoacidsManyneurotransmittersarederivedfromaminoacidsγ-氨基丁酸(γ-aminobutyricacid,GABA)：抑制性神經(jīng)遞質(zhì)，臨床上可用VitB6治療妊娠嘔吐和小兒搐搦Histamine

(組胺)

isapowerfulvasodilator(血管舒張劑),alsostimulatesacidsecretioninthestomachHistaminereceptorantagonistcimetidine西咪替丁，甲腈咪胍(cimetidine)制劑的商品名5-羥色胺5-hydroxytryptamine,5-HT)腦內(nèi)抑制性神經(jīng)遞質(zhì)，外周組織收縮血管牛磺酸(taurine)：膽汁酸的組成成分L-半胱氨酸磺酸丙氨酸?；撬酨olyaminesusedforDNApackaging,isderivedfromMetandornithineSpermidine(精瞇)andspermine(精胺)Decarboxylationofornithine多胺(polyamines)—腐胺，精瞇，精胺Argi