生化生化引论

BiochemistryI上课老师及其联系方式：郑利民 教授；生化系主任Tele-mail:Ls110@李国富 副教授Tele-mail:Ls108@欢迎大家就课程发表您们的想法和意见.

参考课本：1.LehningerPrinciplesofBiochemistry

2.Biochemistry:FifthEdition internationaledition(J.M.Berg,etal)3.王镜岩，生物化学第三版，2002高教出版社课件(slides)会留在计算机中；课前预习和课后及时复习.Wonderfulworld：GardenofEdenDiversityandUnity.Amazing?!..

DefinitionofBiochemistryBiochemistryisthechemistryoflife.

Thestudyofthemolecularbasisoflifeandtheinteractwitheachotherorunderstandinglifephenomenainchemicalterms.Thecombinationofbiologyandchemistryortheapplicationofchemicalprinciplestounderstandbiology..TheChemicalUnityofDiverseLivesLivingorganismsvs.inanimateobjectschemicalcomplexityandorganizationuseenergyinasystemicwayself-replicationandself-assemblyBiochemistryExplains:DiverselivesinunifyingchemicaltermsAllmacromoleculesaremadeofafewsimplecompounds.Musicinourbody!.MainQuestionsforBiochemistryI(thissemester):Whatarethecompositionandstructureofbio-molecules?Howdothesebio-moleculesactandinteractinlivingorganisms？.Allchemicalprocessassociatedwithorganismsatthemolecularlevel-isolatemoleculesanddeterminetheirstructure-analyzetheirfunctionExample:thestudyofDNA

HowlifebeganandevolvedOrganisms:uniformatthemolecularlevel

indicate:theyarosefromacommonancestor

Themainobjectivesaretounderstand.1.ProteinStructureandFunction**

（蛋白质的结构和功能）2.

Enzymes:BasicConceptsandKinetics (酶的基本概念及酶促动力学)3.Enzymes:Catalytic&RegulatoryStrategies （酶催化和调控的策略）4.Carbohydrates（碳水化合物）**5.RNA,DNA,andflowofgeneticinformation** (DNA,RNA及遗传信息的传递)Contentsforthissemester:.6.

LipidsandCellMembranes（脂质和细胞膜）Bio-Signaling(生物信号通路）（Lehninger

和Biochemistry第1-13章）8.

RespondingtoEnvironmentalChanges Thesensorysystems&TheImmunesystem

Biochemistry:Chpt.32&33Contentsforthissemester（续）:.PartIITransducingandStoringEnergy

（能量的转换和贮存）PartIIISynthesizingtheMoleculesofLife

（生物分子的合成）Nextsemester:BiochemistryIITopresentdialogues,actions,stories,anddramawithBiochemicals

.TheAimsofthisCoursesIntroducethelanguageofbiochemistry： --meaning,origin,&significanceofterms2.Understandthephysical,chemical&biologicalcontextofbio-molecule,reaction&pathways3.ThemostimportanttechniquesorExp.forourunderstandingofbiochemistry.BiochemistryAgricultureMolecularBiologyMolecularGeneticsMicrobiologyImmunologyMedicine&Pharmacy(药)ClinicalMedicine临床医学

PreventiveMedicinePathology病理

Pharmacology药理

ApplicationofBiochemistry.BiochemistryandBiotechindustryCellandGeneengineeringPharmaceuticalindustry,proteindrugs,vaccineEnzymeandFermentationengineeringBiochemistryandAgriculturebetterherbicidesandpesticidesgeneticallyengineeredplants.BiochemistryandMedicine

Diagnosis Biochemicalchanges:enzymes,sugaretc ImmunologicalMethods Genediagnosis:chips(Gene&Proteinchips)Therapy Chemotherapy (mostmedicinecurethediseasesbyselectivemodulatehostbiochemicalmetabolite) Genetherapyofcancer,AIDS,geneticdisease.StageI1870s’~1930s’--ChemicalConstitutionofLivingOrganismsStageII1930s’~1950s’--LawofChemicalChangeandControlofDifferentBio-moleculesStageIII1950s’~present--PrinciplesthatareCentralforUnderstandingLivingOrganisms.TheDevelopmentofBiochemistry.ABriefHistoryofBiochemistryoverthelast200years(milestones)1810–30:C,H,O,andNarethemajorsubstancesfromanimalsandplants.Theterm“Protein”wasfirstusedin1838.1850–90:Carbohydrates,lipids,andnucleicacidswererecognized.Theterm“biochemistry”wasformedin1877byHoppe-Seyler.1890s:Yeastextractfermentsugartoalcohol!Enzymescanfunctionincell-freesystem.Theeraofenzymologydeveloped(1894)..1920sJamesSumner:Enzymesareproteins.1940s-1950sAveryandHershey:DNAcarriesthegeneticinformation.1950sFranklin,andWatsonandCrick: DNAisadoublehelix.1960sNirenberg:Geneticcodesdeciphered.1980sCech:RNAhascatalyticactivity (Ribosome)..Pauling thenatureofchemicalbond; thestructureofproteinsand othermacromolecules; theoriesaboutmolecular disease,suchassickle-cell anemia.SomeofNobelLaureatesinthehistoricaldevelopmentofBiochemistry.Krebs:CitricAcidCycle(TCA):animportantwaybywhichthecomplexchemicalprocessesprovidelivingorganismswithhighenergyphosphate.Sanger:SequencingMethodAminoacidsequencingmethodandthecompletesequenceofinsulin.SangerSequencingMethodforDNA.(OswaldAvery,ColinMacleodandMaclynMcCarry)(有荚膜,S;致病性）Avery:DNAcarriesgeneticmaterial.（无荚膜,R；非致病性）.S(heat-killed)Mouselives毒力株经加热灭活后会失去其致病性.R+S(heat-killed/extracts)Mousedies.结果小结和分析

（背景：以往认为蛋白质携带遗传信息）有荚膜的活细菌（S）： 具致病性；无荚膜的活细菌（R）： 无致病性S

菌株加热灭活后： 无致病性灭活后的S菌株＋活细菌R：具致病性！提示 S菌株中的遗传信息被导入活细菌R 该遗传信息对热不敏感，不是蛋白质

未知的物质携带了遗传信息！！.DNAcarriesthegeneticinformation.1869,Miescherisolatesnuclei1944,AverydiscoversthatDNAcarriesthegeneticmaterial1953,WatsonandCrickproposethedouble-helicalstructureofDNAVariousprocessconcernedwithDNA.ex.semi-conservativereplication..DNA,RNAandProteinsynthesisS.Ochoa&A.Kornberg:EnzymaticsynthesisofRNAandDNA(1959).M.W.Nirenberg&H.G.Khorana:Thegeneticcodesinproteinsynthesis(1968).F.Jacob,A.Lwoff,&J.Monod：Mechanismstoswitchon/offgenescells(1965)D.Baltimore,R.Dulbecco,H.M.Temin：Reversetranscriptase

(1975).B.

McClintock:mobilegeneticelements(1983).S.Tonegawa:geneticprincipleforthegeneration ofantibodydiversity(1987).S.Altman&T.R.Cech:RNAcatalyzeRNAprocessing(Ribozyme，1989)R.J.Roberts&P.A.Sharp:eukaryoticgenesare splitandsplicedaftertranscription(1993)M.Rodbell:GTP-bindingproteins(1994).GunterBlobel,intrinsicsignalsgovernprotein localization(1999)..吴宪：与美国哈佛医学院Folin一起首次用比色定量方法测定血糖。回国后与其他科学家在蛋白质变性理论，血液生化，免疫化学，内分泌学等多方面研究作出贡献。上海生化所王应睐等于1965年人工合成具有生物活性的牛胰岛素；1983年完成酵母AlatRNA的人工全合成。AchievementsofChineseBiochemists.ModernBiochemicalScience

commonlanguageofbiology:概念和方法Define

chemicalmechanismsincriticalprocess oflife.

RevealethechemicalunityindiversityoflivesLivingorganisms(e.g.,E.coli&human)aresimilaratthemicroscopicandchemicallevel.ThebuildingblocksformacromoleculesaresameTheflowofgeneticinformationisthesame(fromDNAtoRNAtoprotein)..greatimpactonmedicine&agriculture Causeofdisease,diagnosisandtreatment Rationaldesignofnewdrugs Generationofcropsanddomesticanimals withnew(geneticmodified)featuresCreatenewconcepts&techniquestodealwith theprimaryquestionsinbiology/medicine Mechanismofcelldifferentiation， development，Carcinogenesis Molecularbasisofmemory,thinking…etc.HowtoStudyBiochemistryExamine：Criticalexp.

formajordiscoveriesUnderstand:

Majorthemesinbiochemistry,e.g.,thepropertiesandfunctionsofnon-covalentinteractions,allostericregulation,etc.Getasenseofdevelopingandevolvingconceptsandknowledge.Whatwearelearningtodaymaybemodifiedorcorrectedtomorrow.PartIFoundationsofBiochemistry1.Themolecularlogicoflife2.Bio-molecules3.

Cells4.WaterSomeImportantChemicalConceptsandPrinciplesforStudyingBiochemistry.GeneralFeaturesofLivingOrganismcomplicated&highlyorganizedstructuresmetabolize--usenutrientsandenergyfrom theirenvironmentrespond(adapt/survive)toitssurrounding tofindenergyandrawmaterialsselfreplicateandselfassemblyevolveanddiversifyThemolecularlogicoflife.

ChemicalUnityofDiverseLivingOrganisms

(生命体化学组成上的一致性和多样性)★Composedoflifelessmolecules★Thesemoleculesconformtophysicalandchemicallawswhenexaminedindividually★Livingorganismsmaintainhighlyorderedstatesbyconsuminginanimatematerialsfromenvironment.Alllivingorganismsbuildmoleculesfromthesamekindsofmonomericsubunits..Thestructureofamacromoleculedeterminesitsspecificbiologicalfunction.Eachgenusandspeciesisdefinedbyitsdistinctivesetofmacromolecules.MoleculescontainedinorganismsWater(50-95%)Ions(1%)Organicmolecules(Rest)Livingmatteriscomposedmostlyofthesixlighterelements:

C,H,O,N,P,SH,O,N,andC:thelightestelements(lightestelementsformthestrongestbonds)Bio-molecules.Thetraceelements(Fe,Cu,Mn,Zn,I,Mg)areabsolutelyessentialtolife..Bio-molecules:CompoundsofCarbonCarbon:至少占细胞干重的一半WhyCarbon?versatilebondingcapacityEachCatomcanformverystablesinglebondwith1-4otherCatoms;anddoubleortriplebondsbetweentwoCatoms.CovalentlylinkedCatomscanformdifferentstructures（linear,branched,orcyclic）addingfunctionalgroupsconferringspecificactivitiestothemolecules..Versatilityofcarboninformingcovalentbonds.Organiccompounds:Moleculescontainingcovalentlybondingcarbonbackbones;e.g.alcohols,amines,aldehydes(醛),ketones,羧基,巯基,…etcMostbio-moleculesareorganiccompounds.

“C”:tetrahedralarrangementofitsfoursinglebonds.C-Csinglebondshavefreedomofrotation,butnotdoublenortriplebonds.Nootherchemicalelementhasthecapacitytoformmoleculesofsuchwidelydifferentsizes,shapes,withvarietyoffunctionalgroups..★Mostbiomoleculescanbeconsideredtobederivedfromhydrocarbons★hydrophilicinteractionsbetweenbiomoleculesHydrocarbons.fisherBall-and-stickSpacefillingBio-moleculeshave3-Dstructures.Bio-moleculeshave3-DstructuresThespecialfeatureoforganiccompoundsisNOTtheircompositionsbutthewaytheiratomsarecombined(structures,

1820s)Corollary:twosubstancesmayshowthesamechemicalformulabutphysicallyandchemicallydifferentmaterials(differentstructuresandfunctions)..Conventionusedforconfiguration.Lightabsorbingpigmentinrhodopsinanintegralmembraneprotein.Chiral：手性..Interactionsbetweenbio-moleculesarestereo-specificBetweenpairsofenantiomers对映(结构)体： usuallyonlyoneformisbiologicallyactive. L-aminoacids(S)arefoundinproteins D-glucose(R)isbiologicallyactiveOnlyonechiralformisgeneratedinlivingcellsduetoenzymespecificity(1975NobelPrize)

Incontrast:thetwoenantiomersareusuallysynthesizedinequalamountsinvitrochemicalsynthesis.Conventionfromorganicchemistry.Chewinggums绿薄荷香菜Twostereoisomersmayhavetotallyoppositebiologicaleffects(e.g.,Chewinggums).Neutralsweet天冬酰苯丙氨酸甲酯

Aspartame,asugarsubstitute;itsstereoisomer,bitter.Fourfamilies: Aminoacids；Sugar； Fattyacids；NucleotidesFunctions:Usedtosynthesizelargermolecules；Havespecialbiologicalfunctions；Involvedincomplexreactionpathways；MajorClassesofSmallBio-molecules.Fivegeneraltypesofreactionsincells:Oxidation-reduction(氧化－还原反应)Internalre-arrangements(isomerization,异构)Cleavage&formationof“C-C”bondsGrouptransfer(亲核取代)CondensationBiochemicalReactionSimilartootherchemicalreactions--

brokenandformationofcovalentbonds.Oxidation：gainsoxygenorloseshydrogenReduction：losesoxygenorgainshydrogenOxidation-ReductionReactions.theintra－molecularshiftofatoms/groups

Internalre-arrangements(isomerization,异构)

.Energy：thecentralthemeinBiochemistry

LivingcellsneedaconstantflowofenergytopreventthemfrombecomingdisorderedLivingcellshaveevolvedsubtlemechanismsforgeneratingandusingenergy.AlllifeprocessesconsistofchemicalreactionscatalyzedbyenzymesThereactionsinalivingorganismareknowncollectivelyasmetabolism(代谢）AcquisitionandutilizationofenergySynthesisofmolecules：forcellstructureandfunctioningRemovalofwasteproductsBiochemicalReactioninlife.DefinitionofMetabolismThehighlyintegratednetworkofchemicaltransformations.Degradation(decreasingorder,thusenergyreleasing)toprovideenergy,catabolism;Synthesis(increasingorder,thusenergyconsuming)toprovidebuildingmaterials,anabolism..TheRolesofmetabolismExtractenergyandreducingpowerfromtheenvironment(生命体通过光合作用和氧化作用从外界吸收能并释放废弃物）Generation(interconversion)ofallthebiomoleculesforalivingorganism(biosynthesis).（伴随着物质和能量代谢，生物分子间通过分解和合成作用发生互换）.Anabolism合成代谢Catabolism

分解代谢能源物质中间代谢产物废弃物.GeneralFeaturesofmetabolismlinear,branchedorcircularpathways;Highlyinterconnected

各个途径相互交接，形成物与能的网络化交流系统

Tightlyregulatedtoachievebesteconomy精密调控机制保证机体最经济的利用物质和能量.Alllivingorganismsaremadeupofcells, thesmallestunitboththestructural andfunctionaloflivingmatters.Cellsarecapableofself-reproduction.Mostcellsaremicroscopicinsize Eukaryoticcells:5-100mminsize； bacteria:1-2mm;mycoplasma:0.3mmCell:FundamentalUnitofLife.Prokaryotic(原核）cells:Lackanucleuse.g.,EubacteriaandarchaeaSimplestructure;Abundant&diverseEukaryotic（真核）cellsPossessanucleusboundedbymembrane,containinggeneticinformationintheformofchromosomesComparison:seeTable2-1,p29LehningerTwocategoryofcells.EukaryotesLargerCellvolume；Morecomplicatedcellstructure,withmembrane-boundednucleusandorganelles(细胞器）Energymetabolism:

moreunifiedandpackedinmitochondriaWithcytoskeletonandintracellularmovementCelldividedbymitosisFormmulti-cellularorganisms..AdividingE.coli大肠杆菌.Saccharomycescerevisiae(baker’syeast).★Permittheconcentrationofreactantandproductmolecules★Makeintricateregulatorymechanismpossible★Cellsofmulti-cellulareukaryotesareabletorespondquicklyandeffectivelytotheintercellularcommunicationAdvantagesfromOrganelles.AdvantagesofMulti-cellularorganisms

overunicellularones★Possessarelativelymorestable,controlledenvironmentforcells★Cellshaveadivisionoflaborallowinggreatercomplexityinbothformandfunction★Abletoexploitenvironmentalresourcesmoreeffectively★Theyarehighlyorderedlivingsystems.NucleusStorethegeneticinformationcarrier(DNA)SurroundedbyanNenvelop(doublemembraneswithspecializedpores).TheouterlayeriscontinuouswithERmembranesystem.DNAiscondensed螺旋(compressedabout10millionfoldinthelineardimension)inahumanchromosome染色体..Nuclearporesnucleolus.DNA被螺旋压缩(10millionfold

inthelineardimension)后组成染色体..EndoplasmicReticulum(ER)内质网acontinuousmembranesystemconsistoftubes&flattenedsacsforminganenclosedlumen

Ribosomes(synthesizeproteins)areattachedtothecytoplasmicsurfaceofER,formingtheroughER(RER)structure.

SmoothER(oftentubular)：thesiteforlipidsynthesis；generatestransportvesicles

thatfusewithothermembranesystemsinthecell...GolgiApparatus:processandsortproteinsastackofflattenedmembranesacssurroundedbymanysmallvesicles.structurallyandfunctionallyasymmetric,thecissidefaceER；transfaceplasmamembraneProteinsandlipidsmovethroughGolgi

体,enteringfromthecissideandexitingfromthetransside.Duringthisprocess,theyareextensivelymodified,e.g.,glycosylated

糖基化,sulfated硫酸化,phosphorylated

磷酸化,etc..Mitochondria线粒体

Withasmoothoutermembraneandaninfoldedinnermembrane(formingmanycrista

突起).Hundredsofenzymescatalyzingtheenergywerecontainedwithininnermembrae,andgeneratetheenergycarrier(ATP)ContainsitsownDNA,RNA,ribosomes

核糖体!Itduplicatesitselfwhencelldivides.Playimportantroleincellapoptosis(凋亡）.Lysosomes溶酶体.M吞噬处理入侵细菌及提呈抗原的机制.PlasmamembranePerformsseveralvitalfunctionsforthecell:Transport,whichrequirescarrierandchannelproteinsProvidesmechanicalstrengthandshapetothecellCellcommunicate,responsetoextracellularsignals;specializedfunctionssuchasmusclecontractionandnerveimpulseconduction.Plasmamembraneisalipidbilayercomposedoflipidandproteinmolecules.Others：Peroxisomes过氧化物酶体Chloroplasts叶绿体Thecytoskeletonsystem……etc.Aroughanalogybetweenthethecellandthehumansociety

Nucleus:thehighestadministrativesection.Mitochondriaandchloroplasts:thepowerplant.

GolgiApparatus:thepostofficeCytoskeletonsystem:thehighways(transportation)

Lysosomes:therecyclingcenterER:thefactory，training&educationcenterPlasmamembrane:theborderlineLikethesociety,thecytoplasmiscrowded,highlyorganized,anddynamic..2004年世界十大科技进展新闻是：

1.“勇气”&“机遇”号发现火星有水的证据..ItisNOTanaccidentthatlifearoseinassociationwithwater,sincethissubstancehasseveralunusualpropertiesthatsuitstobethemediumoflifeThermalpropertiesSolventcharacteristicsWater:MediumofLife.

ThermalProperties:

Water’smelting&boilingpointsareexceptionallyhighcomparedwithrelatedmoleculesofsimilarmolecularweight..Water’shighheato