信号通路生物化学Word文件下载.docx
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信号通路生物化学Word文件下载.docx
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Historicalaspects
H.M.Kalckar.1991.50yearsofbiologicalresearch:
FromoxidativephosphorylationtoenergyrequiringtransportregulationAnnu.Rev.Biochem.60:
1-37.(PubMed)
Kalckar,H.M.(Ed.),1969.BiologicalPhosphorylations.PrenticeHall.Fruton,J.S.,1972.MoleculesandLife.Wiley-Interscience.
Lipmann,F.,1971.WanderingsofaBiochemist.Wiley-Interscience.
15.Signal-TransductionPathways:
AnIntroductiontoInformationMetabolism
Acellishighlyresponsivetospecificchemicalsinitsenvironment.Hormonesarechemicalsignalsthattellacelltorespondtoachangeinconditions.Moleculesinfoodoraromascommunicatetasteandsmellthroughtheirinteractionwithspecializedsensorycells.Thischapterprovidesanoverviewofinformationmetabolismhowcellsreceive,process,andrespondtoinformationfromtheenvironment.Theresultsofgenome-sequencingeffortshaveunderscoredhowwidespreadanddiversetheseinformation-processingcircuitsare.Forexample,approximatelyhalfofthe25largestproteinfamiliesencodedbythehumangenomedealprimarilywithinformationprocessing.
Signal-transductioncascadesmediatethesensingandprocessingofstimuli.Thesemolecularcircuitsdetect,amplify,andintegratediverseexternalsignalstogenerateresponsessuchaschangesinenzymeactivity,geneexpression,orion-channelactivity.Thischapterisanintroductiontosomeofthemostimportantclassesofmoleculesthatparticipateincommonsignal-transductionpathways.Wewillencountermanyspecificpathwaysintheirbiochemicalcontextsinlaterchapters.Inthischapter,wewillalsoconsidertheconsequencesofdefectsinthesepathways,particularlythoseleadingtocancer.
15.0.1.SignalTransductionDependsonMolecularCircuits:
AnOverview
Signal-transductionpathwaysfollowabroadlysimilarcoursethatcanbeviewedasamolecularcircuit(Figure15.1).Webeginbyexaminingthechallengesposedbytransferringextracellularinformationtoacell'
sinterior.
1.Membranereceptorstransferinformationfromtheenvironmenttothecell'
sinterior.Afewnonpolarsignalmoleculessuchasestrogensandothersteroidhormonesareabletodiffusethroughthecellmembranesand,hence,enterthecell.Onceinsidethecell,thesemoleculescanbindtoproteinsthatinteractdirectlywithDNAandmodulategenetranscription.Thus,achemicalsignalentersthecellanddirectlyaltersgene-expressionpatterns.TheseimportantsignalingsystemswillbediscussedinChapter31.However,mostsignalmoleculesaretoolargeandtoopolartopassthroughthemembrane,andnoappropriatetransportsystemsarepresent.Thus,theinformationthatsignalmoleculesarepresentmustbetransmittedacrossthecellmembranewithoutthemoleculesthemselvesenteringthecell.Amembrane-associatedreceptorproteinoftenperformsthefunctionofinformationtransferacrossthemembrane.
Suchareceptorisanintrinsicmembraneproteinthathasbothextracellularandintracellulardomains.Abindingsiteontheextracellulardomainspecificallyrecognizesthesignalmolecule(oftenreferredtoastheligand).Suchbindingsitesareanalogoustoenzymeactivesitesexceptthatnocatalysistakesplacewithinthem.Theinteractionoftheligandandthereceptoraltersthetertiaryorquaternarystructureofthereceptor,includingtheintracellulardomain.Thesestructuralchangesarenotsufficienttoyieldanappropriateresponse,becausetheyarerestrictedtoasmallnumberofreceptormoleculesinthecellmembrane.Theinformationembodiedbythepresenceoftheligand,oftencalledtheprimarymessenger,mustbetransducedintootherformsthatcanalterthebiochemistryofthecell.
2.Secondmessengersrelayinformationfromthereceptor-ligandcomplex.Changesintheconcentrationofsmallmolecules,calledsecondmessengers,constitutethenextstepinthemolecularinformationcircuit.ParticularlyimportantsecondmessengersincludecyclicAMPandcyclicGMP,calciumion,inositol1,4,5-trisphosphate,(IP3),anddiacylglycerol(DAG;
Figure15.2).
Theuseofsecondmessengershasseveralconsequences.First,secondmessengersareoftenfreetodiffusetoothercompartmentsofthecell,suchasthenucleus,wheretheycaninfluencegeneexpressionandotherprocesses.Second,thesignalmaybeamplifiedsignificantlyinthegenerationofsecondmessengers.Enzymesormembranechannelsarealmostalwaysactivatedinsecond-messengergeneration;
eachactivatedmacromoleculecanleadtothegenerationofmanysecondmessengerswithinthecell.Thus,alowconcentrationofsignalintheenvironment,evenaslittleasasinglemolecule,canyieldalargeintracellularsignalandresponse.Third,theuseofcommonsecondmessengersinmultiplesignalingpathwayscreatesbothopportunitiesandpotentialproblems.Inputfromseveralsignalingpathway
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- 信号 通路 生物化学