生物化学教学课件：Hormones

Hormones

Tissue-SpecificMetabolism:TheDivisionofLaborEveryprocessinorganismisregulatedbyoneormorehormones.hormonalsignalsintegrateandcoordinatethemetabolicactivitiesofdifferenttissues.Thecoordinationofhormonalsignalsinmammalsisachievedbytheneuroendocrinesystem.1.Hormonesoutline1.1Definition----Hormonesarechemicalmessengerssecretedbycertaintissuesintothebloodorinterstitialfluid细胞间液,servingtoregulatetheactivityofothercellsortissues.1.2Chemicalpropertyofhormonesinvertebratemetabolism(1)peptidesorpolypeptides,suchasinsulinorglucagon(2)aminoacidderivatives,includingthecatecholamines儿茶酚胺andthyroxine甲状腺素(3)steroid,includingglucocorticoids糖皮质激素andthesexhormones(4)脂肪酸衍生物激素－－－PG(前列腺素）1.3secretionofhormonesHormoneissecretedbyendocrineglandEndocrinegland:agroupofcellsandbloodvesselspineal松果体,pituitary垂体,thyroid甲状腺,parathyroid甲状旁腺,pancreas胰岛,adrenals肾上腺,gonad性腺,thymus胸腺TheEndocrineSystem----acollectionofglandsthatsecretehormonesTheendocrinesystemofthepancreasGlucoseregulationofinsulinsecretionbypancreatic

cells.1.4Charactersofhormonemechanism2.MechanismsofHormoneAction

Hormones----•activeatexceedinglylowconcentrations.

•actthroughbindingtospecificreceptors,insidethetargetcelloronthecellsurface•Secondmessengersareoftenusedtotransmitthemessagetothetargetmetabolicpathway（notallhormoneactionsinvolveasecondmessenger）Signaltransduction•informationfromoutsidethecellisconveyedintothecell.•afirstmessenger,ahormone,bindstoacellsurfacereceptor.•Thebindingstimulatesproductionofasecondmessengerinsidethecell.•Thesecondmessengerstimulatereactionsofdownstreamkinasecascade.Hormonereceptorcharacters•macromolecularreceptor•participatesintransductionofthesignals•Theactivityofitsfunctionalsiteisalteredbyhormonebinding•Mosthormonesbindtightlytoitsreceptor,dissociationconstants：0.1M－1.0pM.•Thereceptordensityonacellsurfacedecideitsresponsetohormone.2.1seven-helixreceptorsactivateadenylatecyclase

－－cAMP-ProteinKinasepathwayepinephrine2.1.1seven-helixreceptors–mostnitrogenhormoneReceptorstructure：Middle:7helixN-end:2polysaccarideunitC-end:serresidueGProtein–CoupledReceptor(GPCR)2.1.2Gproteins•namedbasedontheirabilitytobindguaninenucleotides.•Gproteinsaremembraneproteins•inactivestate:bindingGDP,inhibitadenylatecyclase,Gi

activestate:bindingGTP,stimulationofadenylatecyclase,GsGEF:GDP-GTPExchangeFactorGAP:GTP-hydrolysisActivatingProteincholeratoxin2.1.3cAMP--SecondmessengersSecondmessengers:transmitthehormonalmessagetothetargetmetabolicpathway.cAMPisonesuchsecondmessenger2.1.4cAMP-DependentProteinKinase(PKA)1.Activationofadenylatecyclasebyepinephrine肾上腺素

orglucagon胰高血糖素

producescAMP2.promotesthedissociationofcAMP-dependentproteinkinase(R2C2)togivefreecatalyticmonomers(C).3.SubunitCistheproteinkinase,whichphosphorylatesotherproteins.ActivationofcAMP-dependentproteinkinase,PKA.2.1.5PKAactivatesdownstreamKinaseCascadeExample:Glycogenmetabolismisregulatedbyphosphorylation(dephosphorylation)ofasetofproteinsinacascadingmechanismEpinephrineactivatingGlycogenmetabolisminacascademannerCascadeAmplificationHormonesusingcAMPasasecondmessenger:Calcitonin降血钙素(一种调节血中含钙量之荷尔蒙)Chorionicgonadotroptin绒毛膜促性腺激素corticotropin促肾上腺皮质激素epinephrine肾上腺素adrenalinefolliclestimulatinghormoneglucagons胰高血糖素lipotropin促脂素vasopressin抗利尿激素parathyroidhormone副甲状腺素2.2Signaltransductionpathwaysinvolvingphosphoinositide磷酸肌醇turnover2.2.1procedure:a.Hormonebindstoareceptor.b.stimulatesaGproteintobindGTP.c.activatesphospholipaseC磷脂酶Cd.IP3stimulatesthereleaseofcalciumfromitsintracellularstoresintheendoplasmicreticulum.e.DAGstimulatesmembrane-boundproteinkinaseC.

proteinkinaseCrequirescalciumionStimulatingessential:DAGgreatlyincreasetheaffinityoftheenzymeforcalciumions.f.ProteinkinaseCphosphorylatesspecificserineandthreonineresiduesintargetproteins.WhyhasnaturechosenCa2+tomediatesomanysignalingprocess?1.细胞内浓度可发生大幅度改变Cytosolic[Ca2+]<10-7M,lowerthanoutsidethecell传递信号,可于瞬间打开细胞膜/内膜的钙通道骤然升高细胞质中Ca2+的水平.2.Ca2+可与多个配体(6-8个氧原子)结合Ca2+和Pr不同片断发生交联诱导Pr发生巨大的构象变化targetproteinactivitychanges2.3Receptorswithtyrosinekinase1.Epidermalgrowthfactor(EGF表皮生长因子);2.Platelet-derivedgrowthfactor(PDGF血小板生长因子);3.Colony-stimulatingfactor1(CSF-1);4.Fibroblastgrowthfactor(FGF纤维原细胞血小板生长因子);5.InsulinReceptorswithTyrosineKinaseActivity•containanintrinsicenzymaticactivity•phosphorylatestyrosineresidueindownstreamprotein•asinglemembrane-spanningdomain.•nosecondmessengersInsulinpathwayInsulinreceptor:aglycoproteinwithanα2β2tetramericstructureαchaintobindinsulin.βchain,C-terminusinthecellhasaproteintyrosinekinaseactivity

Thekinaseactivityisessentialtothebiologicalactivityoftheinsulinreceptorsomecasesofnon-insulin-dependentdiabetesareassociatedwithreceptormutationsthatabolishthekinaseactivity.2.4SteroidandThyroid甲状腺Hormones--IntracellularReceptorsSteroidsandrelatedhormones(i.e.,thyroid,vitaminD,andretinoicacidhormones)Actwithinthenucleusregulatetranscriptionofspecificgenes(usuallypositively).

Steps:Steroidhormonestransportdirectlyfromoutsideintocytoplasm,thenintonucleusbindtospecificreceptorproteinsinthenucleusreceptor-hormonecomplexesinteractwithspecificDNAsequences---hormoneresponsiveelements(HREs).regulatetranscriptionofspecificgenes.SteroidHormonesreceptorscontainboundzincandconservedcysteineresiduesessentialforDNAbinding.

-----"zincfinger"structuralmotifEffectsoccurringviamembranereceptors:shortduration---representresponsestorapidandurgentphysiologicaldemandsandinvolveactivationorinhibitionofpreexistingenzymes.Effectsofsteroids:longer-termchanges3.HormonalRegulationandIntegrationofMammalianMetabolismThemajorendocrinesystemsandtheirtargettissuesp270HormoneReleas