生物化学理论课件中科大绪论.ppt
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生物化学理论课件中科大绪论.ppt
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生物化学Biochemistry周丛照李卫芳2008年9月1日,绪论大纲:
课程主要内容及要求引子:
生物化学的历史和发展趋势,教材:
生物化学,第三版,王镜岩等主编,2002年,高教出版社参考书:
1.Biochemistry,JeremyM.BergJohnL.TymoczkoLubertStryer5theditionW.H.FreemanandCompany2.Biochemistry,DonaldVoet,JudithG.Voet.3rdedition,2003,JohnWiley&Sons,Inc.NewYork.,生物化学(上)54学时第一章绪论(2学时)(周丛照)第二章蛋白质(16学时)(周丛照)2.120种氨基酸的结构和性质(2学时)2.2蛋白质中的共价结构(2学时)2.3蛋白质的高级结构(2学时)2.4血红蛋白的结构与功能(2学时)2.5维持蛋白质高级结构的作用力(2学时)2.6蛋白质折叠和结构进化(2学时)2.7蛋白质分离纯化(4学时)第三章核酸(6学时)(李卫芳)3.1核苷酸的结构和性质(2学时)3.2核酸的双螺旋结构(1学时)3.3维持核酸高级结构的作用力(2学时)3.4超螺旋结构(1学时),第四章糖(4学时)(李卫芳)4.1糖的生物学作用(1学时)4.2单糖和多糖(2学时)4.3糖蛋白(1学时)第五章脂类和生物膜(6学时)(李卫芳)5.1脂的分类和性质(2学时)5.2生物膜(2学时)5.3膜蛋白(2学时),第六章酶(14学时)(李卫芳)6.1酶的作用特征(2学时)6.2酶的分类(1学时)6.3酶活力测定(2学时)6.4酶促反应动力学(3学时)6.5影响酶作用的因素(2学时)6.6酶催化作用机理(2学时)6.7结构酶及其作用原理(2学时)第七章维生素与激素(6学时)(周丛照)7.1维生素与辅酶(2学时)7.2激素概述(2学时)7.3激素作用原理(2学时),生物化学(下)36学时第八章代谢总论(2学时)第九章生物膜和物质运输(2学时)第十章糖酵解(6学时)第十一章柠檬酸循环(6学时)第十二章氧化磷酸化(5学时)第十三章光合作用(2学时)第十四章糖原的分解和生物合成(5学时)第十五章脂肪酸代谢(4学时)第十六章氨基酸的分解代谢(2学时)第十七章核酸代谢(2学时),WhatisBiochemistry?
thestudyofthosemoleculesusedandmanufacturedbylivingthings.,Threeaspectsofbiochemistry:
1)Biochemistryisconcernedwithstructuralchemistry.Itseekstodeterminethestructuresofmoleculesfoundinlivingsystemsinordertounderstandstructure-functionrelationships.,2)Biochemistryisconcernedwithchemicalchange,thisisreflectedinthestudyofmetabolicpathways,3)BiochemistryisconcernedwithinformationwhichhasaccumulatedthroughevolutionandispreservedinDNA(orsometimesRNA).Thesenucleicacidsequencescodeforaminoacidsequences,whichresultinfoldedproteins.Theseproteinsareoftencatalysts(enzymes)andsomeofthemareregulated(abletosensethechemicalstateinsidethecelland,insomecases,theoutside),BiochemistrythroughevolutionHowtobuildalifewithmolecules?
OrTheMolecularDesignofLife,Fourtransitionsthroughevolution:
1,chemicals,micromolecules2,macrobiomolecules3,energy4,stressresponse,Theevolutionofliferequiredaseriesoftransitions,beginningwiththegenerationoforganicmoleculesthatcouldserveasthebuildingblocksforcomplexbiomolecules.,Thenextmajortransitionintheevolutionoflifewastheformationofreplicatingmolecules.EvolutionRequiresReproduction,Variation,andSelectivePressure,Replication,coupledwithvariationandselectivepressure,markedthebeginningofevolution.Variationwasintroducedbyanumberofmeans,fromsimplebasesubstitutionstotheduplicationofentiregenes.RNAappearstohavebeenanearlyreplicatingmolecule.Furthermore,someRNAmoleculespossesscatalyticactivity.However,therangeofreactionsthatRNAiscapableofcatalyzingislimited.Withtime,thecatalyticactivitywastransferredtoproteins,linearpolymersofthechemicallyversatileaminoacids.RNAdirectedthesynthesisoftheseproteinsandstilldoesinmodernorganismsthroughthedevelopmentofageneticcode,whichrelatesbasesequencetoaminoacidsequence.Eventually,RNAlostitsroleasthegenetothechemicallysimilarbutmorestablenucleicacidDNA.Inmodernorganisms,RNAstillservesasthelinkbetweenDNAandprotein.,EnergyTransformationsAreNecessarytoSustainLivingSystemsAnothermajortransitioninevolutionwastheabilitytotransformenvironmentalenergyintoformscapableofbeingusedbylivingsystems.ATPservesasthecellularenergycurrencythatlinksenergy-yieldingreactionswithenergy-requiringreactions.ATPitselfisaproductoftheoxidationoffuelmolecules,suchasaminoacidsandsugars.Withtheevolutionofmembraneshydrophobicbarriersthatdelineatethebordersofcellsiongradientswererequiredtopreventosmoticcrises.ThesegradientswereformedattheexpenseofATPhydrolysis.Later,iongradientsgeneratedbylightortheoxidationoffuelmoleculeswereusedtosynthesizeATP.,CellsCanRespondtoChangesinTheirEnvironmentsThefinaltransitionwastheevolutionofsensingandsignalingmechanismsthatenabledacelltorespondtochangesinitsenvironment.Thesesignalingmechanismseventuallyledtocell-cellcommunication,whichallowedthedevelopmentofmore-complexorganisms.Therecordofmuchofwhathasoccurredsincetheformationofprimitiveorganismsiswritteninthegenomesofextantorganisms.,HistoryofBiochemistry(upto1982),1835JonsBerzeliuschemicalcatalysis,usesamylase(淀粉酶)asanexample.1859CharlesDarwinpublishesOntheOriginofSpecies.LouisPasteurfermationcatalyzedbyenzymes,essenceofyeast.1865GregorMendelpublisheshistheoryofgenetics.1869FredrickMeischerdiscoversDNAincellnuclei.EduardandHansBuchnerextractsmaterielfromyeast,conversionofglucosetoalcohol.,1914FritzLipmann,theroleofATPinenergymetabolism.1926JamesSumner,crystallinejackbean(刀豆)urease,isaprotein.1926ThomasHuntMorganwritesTheTheoryoftheGene.1934ArnoldBeckmandevelopesthefirstpHmeter.1937HansKrebsdiscoversthecitricacidcycle(TCAcycle).1941GeorgeBeadle&EdwardTatum,theone-gene,one-enzymehypothesis.OswaldAvery,ColinMacLeod,andMaclynMcCarthyDNAisthegeneticmaterial.,1950EdwinChargaffA=T,G=C(Chargaffsrules).1952LinusPaulingandRobertCorey-helixandthe-pleatedsheet1953JamesWatsonandFrancesCrickthedoublehelixmodelofDNA.1953FredrickSangerthefirstaminoacidsequenceofaprotein(insulin).1956EarlSutherlandisolatescyclicAMP.1957MatthewMeselsonandFranklinStahlsemiconservativeDNAreplication.,1960JohnKendrewandMaxPertuzobtainthefirst3-Dstructureofproteins(hemoglobinandmyoglobin).1960JeraldHuritzandSamuelWeissdiscoverRNApolymerase.1961FrancoisJacobandJaquesMonodpropoundtheoperonmodelofgenecontrol.1963Jean-PierrreChanguex,F.Jacob,andJ.MonodAllostericmodelforinhibitionofenzymes1964SeveralgroupsAcrylamidegelelectrophoresisofproteinsisdeveloped,MarshalNirenberg,H.GobindKhorana,andSeveroOchoacompletetheelucidationofthegeneticcode1965DavidPhillips3-Dmodeloffirstenzyme(lysozyme)1965RobertHolleydeterminesthestructureofatransfer-aaRNA.1965JeromeVinograddiscoverssuperhelicaltwisting.1968MarkPtashneandWalterGilbertidentifythefirstrepressorgenes1969Firstsynthesisofanenzyme(ribonuclease).,1970HamiltonSmithdiscoversrestrictionendonucleases.1970HowardTeminandDavidBaltimorediscoverreversetranscriptase.1973StanleyCohenandHerbertBoyerpreparerecombinantDNA.1974Sung-HouKim,etal.producethefirstX-raystructureoftransferRNA.1977CesarMilsteindiscovershowtoproducemonoclonalantibodies.1977AllanMaxamandWalterGilbertdevelopachemistryforsequencingDNA.1977FredrickSanger,S.NicklenandA.R.CoulsondevelopachemistryforsequencingDNA.1977PhillipSharpandRichardRobertsdiscoverintrons(interveningsequences).1982AmzelLM,McKinneyM,NarayananP,PedersenPLFirstx-raystructureofamembraneprotein(9).,1980sandearly1990sWonderfultimeforMolecularBiology,HumanGenomeProject(1988-),CentralDogma(CrickF.1958),MolecularBiology,Omics:
MetabolomicsTranscriptomicsProteomicsStructuralGenomics(1998-),Genomics,TheeraofOmics:
(1998-2003orlater?
)Omics=Oh!
Mix!
(millenniumchaos?
),WhatisStructuralGenomics?
Itisanapproachaimingatsolving3-Dstructuresoftheproteinsencodedbyanentiregenome.,KimSH.NatureStructuralBiology1998,OriginalgoalsofSG:
1,toestablishacatalogue/libraryofallfoldscoveringtheentireproteinuniverse2,tohelptheannotationofsequencedgenomes,InternationalStructuralGenomicsProjectsUSAandCanada:
(1998-)9NIHStructuralGenomicsCentersEU:
France(3centers:
Paris-Sud,Marseille,Strasbourg)Germany(StructuralGenomicsFactory)UK(2centers)(SPINE:
StructuralProteomicsinEurope,2001-)Asia:
Japan(RIKEN)China(Yun-YuSHI;ZiheRAO)(2002-)Korea:
Israel:
WeizmannStructuralProteomicsCenter,Flowchart:
1,Targetsselection:
Bioinformatics2,PCRandcloning:
MolecularBiology3,Proteinproduction:
Biochemistry4,Datacollection(X-raydiffraction/NMR)5,Structuredetermination:
StructuralBiology6,Functioninterpretation:
GeneralBiology,Corecharacteristics:
Highthroughput(hundredstothousandssamples)Large-scale(milligramlevelofproteinsample)Multi-disciplineintegration(frommolecularbiologytostructuralbiology),highthroughputparallelization(平行化)miniaturization(微量化)automation(自动化),cloningrobot:
500-1000clones/3dayscrystallizationrobot:
96x3drops/15minproteinsampleforcrystallizationtrialsinnanolitervolumes(10nl),HansenCL.etal.PNAS;2002,ZhouCZ2004,Differenttagswillmakethedifference,DifferentE.colistrains(DE3series)BL21(DE3)BL21-pLysSRosettaRosetta-pLysSGoldBL21-Codon-plusTunerStar,Co-expressionwithchaperones(DnaK-DnaJ-GrpEand/orGroEL-GroES)MainlyworksforthosepartiallysolubletargetsCo-purificationofchaperoneswiththetargetproteinRe-aggregation/precipitationafterremovalofchaperones,Eukaryoticexpressionsystems(post-translationalmodifications)PichiapastorisSaccharomycescerevisiaeInsectcellsCelllinesVirus-mediatedQuantityandCost-effectivity,DNAshufflingSaturationmutagenesisError-pronePCRToimprove:
thesolubility,activityand/orstability,Reetz,PNAS;2004,invitro/directedevolution,Proteinssamplesforcrystallizationtrials:
1,pureandhomogenous2,stableinsolutionoflowsaltconcentration,properpHandreductant(BME,DTTorTCEP)3,athighconcentration(normally10mg/ml),ProteinsamplesforNMRdatacollection:
1,doublelabelingwith13Cand15N2,nooligomerizationoraggregation3,stableforatleastoneweekatRTor4C4,highexpressionlevel(cost-effective),Optimizationofxtals:
1,abouthalfofthextalswillnotdiffractat3orhigherresolution2,parameters:
saltconcentration,buffersystem,pH,divalentortrivalentirons3,precipitants:
PEGs,MPD,salt,alcohol,4,ligandsorsubstrates/products/analogs5,proteinornucleicacidpartners,Datacollection:
X-raydiffraction:
in-houseX-
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