上海交大生化课件.docx

上海交大生化课件.docx

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上海交大生化课件

Chapter17

Metabolism:

BasicConceptsandDesign

Definition

theclassicdefinition:

Thetotalityofthechemicalreactionsandphysicalchangesthatoccurinlivingorganisms,comprisinganabolism合成代谢andcatabolism分解代谢

themodernone:

（Fromtheviewofthebasicstrategy要略orthreekeyelements要素ofmetabolism:

energy,reducingpower还原力andbuildingblock构建元件）：

⏹Metabolismisageneraltermofahighlyintegratednetworkofchemicalreactions高度整合（协调,统一）的化学反应网络bywhichlivingcellsextractenergyandreducingpowerfromtheirenvironmentandsynthesizethebuildingblocksoftheirmacromolecules.1.从环境汲取能量和还原力2.合成生物大分子的构建元件

Pathways代谢途经（由首尾相接的化学反应组成）Manyofthesereactionsareorganizedintopathways.Eachbiochemicalpathwayconsistsofseveralreactionsthatoccursequentially;thatis,theproductofonereactionisthesubstratefortheonethatfollows.化学反应—（代谢途经）—网络（“点”,“线”,“面”关系）

Twomajortypesofthepathways:

（1）Anabolic合成orbiosyntheticones:

⏹Largecomplexmoleculesaresynthesizedfromsmallerprecursors从较小的前体合成复杂的大分子

Buildingblockmolecules（e.g.,aminoacids,sugars,andfattyacids）producedoracquiredfromthediet（i.e.‘environment’）areincorporatedintolarger,morecomplexmolecules（i.e.‘macromolecules’）即从“构建元件”合成“大分子”

⏹Becausebiosynthesisincreasesorder有序度andcomplexity复杂性（macromoleculesaremoreorderlyandmorereductive还原）,anabolicpathwaysrequirefreeenergy消耗自由能

⏹Examples:

synthesisofpolysaccharides多糖andproteinsfromsugarsandaminoacids,respectively

⏹

（2）Catabolic分解ones:

⏹Largecomplexmoleculesaredegradedintosmaller,simplerproducts.Someofthemreleasefreeenergy.释放自由能

⏹Examples:

β-oxidation（fattyacidsaredegradedintoacetyl-CoA乙酰辅酶A）.

⏹Theprimaryfunctionsofmetabolismare

⏹acquisitionandutilizationofenergy

⏹synthesisofmacromoleculesforcellstructureandfunctioning（i.e.,proteins,nucleicacids,lipids,andcarbohydrates）

⏹removalofwasteproducts.

⏹Metabolismhasacoherentdesigncontainingmanycommonmotifs代谢包含许多共同的模式（框架）:

⏹Thenumberofreactioninmetabolismislargebutthenumberofkindsofreactionsisrelativelysmall.反应类型都少

⏹Themechanisms机制ofthesereactionsareusuallyquitesimple.（e.g.,adoublebondisoftenformedbydehydrationofanalcohol双键由醇脱水形成）反应机制都简单

⏹Agroupofabout100molecules（“centralmolecules”）playsacentralroleinallformsoflife.（e.g.,acetylCoA,G-6-P葡萄糖-6-磷酸,pyruvate丙酮酸,NADH烟酰胺腺嘌呤二核苷酸）相同的中心分子

⏹Metabolicpathwaysareregulatedincommonways.（e.g.,allostericinteraction变构作用ofPFK磷酸果糖激酶;covalentmodification共价修饰ofglycogenphosphorylase糖原磷酸化酶）共同的调控模式

Athermodynamicallyunfavorablereactioncanbedrivenbyafavorableone

Thecriterionofjudgmentwhetherareactioncanoccurspontaneosly:

onlyif△G（thechangeinfreeenergy）isnegative.反应是否能自发进行的判据是△G

△G=△G0+RTln[C][D]/[A][B]Thus,the△Gofareactiondependson:

1.thenatureofthereactants（i.e.△G0,thestandardfree-energychange）2.theirconcentrations

Thestandardfree-energychangeatpH7isdenotedby△G0’.

Animportantthermodynamicfactisthatoverallfree-energychangeforachemicallycoupledseriesofreactionsisequaltothesumofthefree-energychangesoftheindividualsteps偶联的化学反应序列总的自由能改变等于各单步反应自由能改变之和.

⏹HeretheuphillandthedownhillreactionsarecoupledbythesharedchemicalintermediateB共同中间化合物B.

A≒B+CB≒D/A≒C+D

Theothertwoprincipalwaysofthecouplingare

⏹activatedproteinconformation构象.Hereproteinsserveasenergyconversiondevices.Molecularmotorsconvertthephosphorylpotential磷酸基团转移势能ofATPintomechanicalenergy（e.g.myosin肌动蛋白）.TheactivetransportofNa+andK+acrossmembranesisdrivenbythephosphorylationofthesodium-potassiumpump钠钾泵byATPanditssubsequentdephosphorylation去磷酸化

⏹Ionicgradient离子梯度acrossmembranes:

proton质子gradientproducedbytheoxidationoffuelmoleculesorbyphotosynthesisultimatelypowersthesynthesisofmostofATPincells.

“偶联”的概念被极度放大

Conclusion:

Tightcouplingisageneralcharacteristicofbiologicalassemblies复合体（e.g.,theabove-mentionedNa+-K+pumpandtheelectrontransportchain电子传递链）thatmediateenergyconversion.

ATPistheuniversalcurrency通用货币offreeenergyinbiologicalsystems

Nonbiologicsystemmayutilizeheatenergytoperformwork,butbiologicsystemisessentiallyisothermic等温的andusechemicalenergy（especiallyATP）topowerlivingprocesses.

Theuseoffreeenergy:

motion运动,activetransport主动转运,biosynthesis生物合成,signalamplification信号放大

Thesourceoffreeenergy:

oxidationoffoodstuffs（animals）,lightenergy（plants）.

Partoftheabsorbedfreeenergyistransformedintoahighlyaccessible可用的form—ATP（adenosinetriphosphate腺苷三磷酸）containing

⏹adenine腺嘌呤

⏹ribose核糖

⏹andthreephosphategroups（designatedbyadenosine-P~P~P）

⏹ItsactiveformisusuallyacomplexofATPwithMg2+orMn2+.

ATPisanenergy-richmoleculebecauseitstriphosphateunitcontainstwophosphoanhydridebonds磷酸酸酐键

⏹SincelargeamountoffreeenergyisliberatedwhenATPishydrolyzedto（ADP+Pi）orto（AMP+PPi）（pyrophosphate焦磷酸）A—P～P～P→A—P～P+Pi（orA—P+PPi）

⏹ATPallowsthecouplingofthermodynamicallyunfavorablereactions热力学上不可行的反应tofavorableones

⏹△G0’forbothoftheabove-mentionedhydrolyses水解作用is

－7.3kcal/mol

⏹Undertypicalcellularconditions,theactual△Gforthesehydrolysesisabout－12kcal/mol（浓度因素）

⏹Inturn,ATPisformedfromADPandPiinoxidativephosphorylation氧化磷酸化

ThisATP-ADPcycleisthefundamentalmodeofenergyexchangeinbiologicalsystem.

ATPiscontinuouslyformedandconsumed

ATPistheprincipalimmediatedonor即刻供体offreeenergyinbiologicalsystems

⏹100-metersprint短跑isagoodexampletoillustratetheconcept‘immediate’

⏹TherunnerispoweredbyATPduringthefirstsecondandbycreatinephosphate磷酸肌酸duringthefirstfourseconds

⏹andhereafterbyanaerobicglycolysis厌氧酵解ofmuscleglycogen肌糖原

⏹whichmeansthatthestorageofATPinhumanbodiesisquitelimited（enoughtokeepstrenuousexertiononlyforonesecond）

⏹Thelong-termstorageoffreeenergyisfatinadiposetissue脂肪组织ATP→磷酸肌酸→肌糖原厌氧酵解→脂肪分解

Inatypicalcell,theATPmoleculeisconsumedwithinaminutefollowingitsformation.Theturnover转换ofATPisveryhigh,i.e.,ATPiscontinuously（orceaselessly）formedandconsumed

⏹Whenorganismisinthestateofstrenuousexertion,theextant现存的ATPisconsumedupatonceanditbeginstousetheATPconvertedfrom（intheorderof）creatinephosphate,glycogen,andfat（mainlytriglyceride甘油三酯）

⏹Arestinghumanconsumesabout40kgofATPin24h.Duringstrenuousexertion,therateofutilizationofATPmaybeashighas0.5kg/min

⏹AllactivitiesoflivingorganismsneedcontinuoussupplyofATP

⏹Theenergyfromlightoroxidationoffuelmoleculesfirstpumpsprotonsacrossamembrane（typicallytheinnermembraneofmitochondrion线粒体内膜）togenerateaproton-motiveforceandtheprotongradient质子梯度thenpowersthesynthesisofATP.

Structuralbasisofthehighphosphoryltransferpotential磷酰基转移潜势ofATP

ThehydrolysisofATPcanproducearatherhighstandardfreeenergy（△G0’=－7.3kcal/mol）,i.e.,ATPhasastrongertendencytotransferitsterminalphosphorylgrouptowater

Inotherwords,ATPhasahigherphosphorylpotential（phosphorylgroup-transferpotential）

⏹than（e.g.）glyceral3-phosphate3-磷酸甘油,G-6-P,etc.

ThestructuralbasisofthehighphosphorylpotentialofATPisitsstructuralspeciality.Twofactorsareimportant:

⏹electrostaticrepulsion静电斥力（比较ATP和ADP）

⏹resonancestabilization共振稳定作用（酸酐键的共振稳定性小于磷酯键）（比较高能键侧的磷酸和正磷酸

BesidesATPtherearevariousothercompoundsinbiologicalsystemswhichhaveahighphosphorylpotential.AmongthemthefollowingshaveahigherphosphoryltransferpotentialthandoesATP:

⏹PEP烯醇丙酮酸磷酸

⏹carbamoylphosphate氨甲酰磷酸

⏹acetylphosphate乙酰磷酸

⏹creatinephosphate

⏹SoPEPcantransferitsphosphorylgrouptoADPtoproduceATP.

PEP+ADP+H+→pyruvate+ATP.Infact,thisisthefinalstepofglycolysis.

ItissignificantthatATPisinthemiddleamongthebiologicallyimportantphosphorylatedmolecules

Thisintermediateposition（i.e.‘fallshortofthebestbutberatherthantheworst’比上不足比下有余）enablesATPtobeanextremelyimportantcarrierofphosphorylgroup

⏹ATPcantransferittotheotherphosphatecompoundswhichhavealowerphosphorylgrouptransferpotential

⏹andinturnADPcanreceivethegroupfromthehighenergyphosphatecompoundswithahigherpotentialthanATP.

Creatinephosphateisareservoirof~Pinmuscle

TheamountofATPinmuscleisratherlimitedandisonlyenoughtomaintaincontractileactivityforabout1second

⏹Vertebrate脊椎动物musclecontainsareservoirofhigh-potentialphosphorylgroupsintheformofcreatinephosphate

⏹forinvertebrates,thecorrespondingoneisphosphoarginine磷酸精氨酸

⏹whichcanreadilytransferitsphosphorylgrouptoproduceATP

⏹AtpH7,△G0’ofhydrolysisofcreatinephosphateis

－10.3kcal/mol,sofor

creatinephosphate+ADP+H+≒ATP+creatine;thetotalreaction△G0’=－10.3－（－7.3）=－3kcal/mol

⏹TheabundanceofcreatinephosphateanditshighphosphoryltransferpotentialrelativetothatofATPmakeitahighlyeffective~P（high-energyphosphatebond）buffer

⏹ItmaintainsahighconcentrationofATPduringperiodsofmuscularexertion

⏹Indeed,itisthemajorsourceof~Pforarunnerduringthefirstfoursecondsofa100-metersprint.

ATPhydrolysisshiftstheequilibriaofcoupledreactionsbyafactor108

ToenhanceanunderstandingoftheroleofATPinenergycouplingwe’llillustrateitwithachemicalreactionthatisthermodynamicallyunfavorablewi