生化鄭利民生化引論－鄭利民第1頁/共108頁BiochemistryI第2頁/共108頁Wonderfulworld：GardenofEdenDiversityandUnity第3頁/共108頁Amazing?!第4頁/共108頁第5頁/共108頁

DefinitionofBiochemistryBiochemistryisthechemistryoflife.

Thestudyofthemolecularbasisoflifeandtheinteractwitheachotherorunderstandinglifephenomenainchemicalterms.Thecombinationofbiologyandchemistryortheapplicationofchemicalprinciplestounderstandbiology.第6頁/共108頁TheChemicalUnityofDiverseLivesLivingorganismsvs.inanimateobjectschemicalcomplexityandorganizationuseenergyinasystemicwayself-replicationandself-assemblyBiochemistryExplains:DiverselivesinunifyingchemicaltermsAllmacromoleculesaremadeofafewsimplecompounds第7頁/共108頁Musicinourbody!第8頁/共108頁MainQuestionsforBiochemistryI(thissemester):Whatarethecompositionandstructureofbio-molecules?Howdothesebio-moleculesactandinteractinlivingorganisms？第9頁/共108頁Allchemicalprocessassociatedwithorganismsatthemolecularlevel-isolatemoleculesanddeterminetheirstructure-analyzetheirfunctionExample:thestudyofDNA

HowlifebeganandevolvedOrganisms:uniformatthemolecularlevel

indicate:theyarosefromacommonancestor

Themainobjectivesaretounderstand第10頁/共108頁1.ProteinStructureandFunction**

（蛋白質(zhì)的結(jié)構(gòu)和功能）2.

Enzymes:BasicConceptsandKinetics (酶的基本概念及酶促動力學)3.Enzymes:Catalytic&RegulatoryStrategies （酶催化和調(diào)控的策略）4.Carbohydrates（碳水化合物）**5.RNA,DNA,andflowofgeneticinformation** (DNA,RNA及遺傳信息的傳遞)Contentsforthissemester:第11頁/共108頁6.

LipidsandCellMembranes（脂質(zhì)和細胞膜）Bio-Signaling(生物信號通路）（Lehninger和Biochemistry第1-13章）8.

RespondingtoEnvironmentalChanges Thesensorysystems&TheImmunesystem

Biochemistry:Chpt.32&33Contentsforthissemester（續(xù)）:第12頁/共108頁PartIITransducingandStoringEnergy

（能量的轉(zhuǎn)換和貯存）PartIIISynthesizingtheMoleculesofLife

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

第13頁/共108頁TheAimsofthisCoursesIntroducethelanguageofbiochemistry： --meaning,origin,&significanceofterms2.Understandthephysical,chemical&biologicalcontextofbio-molecule,reaction&pathways3.ThemostimportanttechniquesorExp.forourunderstandingofbiochemistry第14頁/共108頁BiochemistryAgricultureMolecularBiologyMolecularGeneticsMicrobiologyImmunologyMedicine&Pharmacy(藥)ClinicalMedicine臨床醫(yī)學

PreventiveMedicinePathology病理

Pharmacology藥理

ApplicationofBiochemistry第15頁/共108頁BiochemistryandBiotechindustryCellandGeneengineeringPharmaceuticalindustry,proteindrugs,vaccineEnzymeandFermentationengineeringBiochemistryandAgriculturebetterherbicidesandpesticidesgeneticallyengineeredplants第16頁/共108頁BiochemistryandMedicine

Diagnosis Biochemicalchanges:enzymes,sugaretc ImmunologicalMethods Genediagnosis:chips(Gene&Proteinchips)Therapy Chemotherapy (mostmedicinecurethediseasesbyselectivemodulatehostbiochemicalmetabolite) Genetherapyofcancer,AIDS,geneticdisease第17頁/共108頁StageI1870s’~1930s’--ChemicalConstitutionofLivingOrganismsStageII1930s’~1950s’--LawofChemicalChangeandControlofDifferentBio-moleculesStageIII1950s’~present--PrinciplesthatareCentralforUnderstandingLivingOrganisms.TheDevelopmentofBiochemistry第18頁/共108頁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).第19頁/共108頁1920sJamesSumner:Enzymesareproteins.1940s-1950sAveryandHershey:DNAcarriesthegeneticinformation.1950sFranklin,andWatsonandCrick: DNAisadoublehelix.1960sNirenberg:Geneticcodesdeciphered.1980sCech:RNAhascatalyticactivity (Ribosome).第20頁/共108頁Pauling thenatureofchemicalbond; thestructureofproteinsand othermacromolecules; theoriesaboutmolecular disease,suchassickle-cell anemia.SomeofNobelLaureatesinthehistoricaldevelopmentofBiochemistry第21頁/共108頁Krebs:CitricAcidCycle(TCA):animportantwaybywhichthecomplexchemicalprocessesprovidelivingorganismswithhighenergyphosphate.Sanger:SequencingMethodAminoacidsequencingmethodandthecompletesequenceofinsulin.SangerSequencingMethodforDNA第22頁/共108頁(OswaldAvery,ColinMacleodandMaclynMcCarry)(有莢膜,S;致病性）Avery:DNAcarriesgeneticmaterial第23頁/共108頁（無莢膜,R；非致病性）第24頁/共108頁S(heat-killed)Mouselives毒力株經(jīng)加熱滅活后會失去其致病性第25頁/共108頁R+S(heat-killed/extracts)Mousedies第26頁/共108頁結(jié)果小結(jié)和分析

（背景：以往認為蛋白質(zhì)攜帶遺傳信息）有莢膜的活細菌（S）： 具致病性；無莢膜的活細菌（R）： 無致病性S

菌株加熱滅活后： 無致病性滅活后的S菌株＋活細菌R：具致病性！提示 S菌株中的遺傳信息被導(dǎo)入活細菌R 該遺傳信息對熱不敏感，不是蛋白質(zhì)

未知的物質(zhì)攜帶了遺傳信息?。〉?7頁/共108頁DNAcarriesthegeneticinformation第28頁/共108頁1869,Miescherisolatesnuclei1944,AverydiscoversthatDNAcarriesthegeneticmaterial1953,WatsonandCrickproposethedouble-helicalstructureofDNAVariousprocessconcernedwithDNA.ex.semi-conservativereplication.第29頁/共108頁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)第30頁/共108頁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).第31頁/共108頁吳憲：與美國哈佛醫(yī)學院Folin一起首次用比色定量方法測定血糖?；貒笈c其他科學家在蛋白質(zhì)變性理論，血液生化，免疫化學，內(nèi)分泌學等多方面研究作出貢獻。上海生化所王應(yīng)睞等于1965年人工合成具有生物活性的牛胰島素；1983年完成酵母AlatRNA的人工全合成。AchievementsofChineseBiochemists第32頁/共108頁ModernBiochemicalScience

commonlanguageofbiology:概念和方法Define

chemicalmechanismsincriticalprocess oflife.RevealethechemicalunityindiversityoflivesLivingorganisms(e.g.,E.coli&human)aresimilaratthemicroscopicandchemicallevel.ThebuildingblocksformacromoleculesaresameTheflowofgeneticinformationisthesame(fromDNAtoRNAtoprotein).第33頁/共108頁greatimpactonmedicine&agriculture Causeofdisease,diagnosisandtreatment Rationaldesignofnewdrugs Generationofcropsanddomesticanimals withnew(geneticmodified)featuresCreatenewconcepts&techniquestodealwith theprimaryquestionsinbiology/medicine Mechanismofcelldifferentiation， development，Carcinogenesis Molecularbasisofmemory,thinking…etc第34頁/共108頁HowtoStudyBiochemistryExamine：Criticalexp.

formajordiscoveriesUnderstand:

Majorthemesinbiochemistry,e.g.,thepropertiesandfunctionsofnon-covalentinteractions,allostericregulation,etc.Getasenseofdevelopingandevolvingconceptsandknowledge.Whatwearelearningtodaymaybemodifiedorcorrectedtomorrow第35頁/共108頁PartIFoundationsofBiochemistry1.Themolecularlogicoflife2.Bio-molecules3.

Cells4.WaterSomeImportantChemicalConceptsandPrinciplesforStudyingBiochemistry第36頁/共108頁GeneralFeaturesofLivingOrganismcomplicated&highlyorganizedstructuresmetabolize--usenutrientsandenergyfrom theirenvironmentrespond(adapt/survive)toitssurrounding tofindenergyandrawmaterialsselfreplicateandselfassemblyevolveanddiversifyThemolecularlogicoflife第37頁/共108頁

ChemicalUnityofDiverseLivingOrganisms

(生命體化學組成上的一致性和多樣性)★Composedoflifelessmolecules★Thesemoleculesconformtophysicalandchemicallawswhenexaminedindividually★Livingorganismsmaintainhighlyorderedstatesbyconsuminginanimatematerialsfromenvironment第38頁/共108頁Alllivingorganismsbuildmoleculesfromthesamekindsofmonomericsubunits.第39頁/共108頁Thestructureofamacromoleculedeterminesitsspecificbiologicalfunction第40頁/共108頁Eachgenusandspeciesisdefinedbyitsdistinctivesetofmacromolecules第41頁/共108頁MoleculescontainedinorganismsWater(50-95%)Ions(1%)Organicmolecules(Rest)Livingmatteriscomposedmostlyofthesixlighterelements:

C,H,O,N,P,SH,O,N,andC:thelightestelements(lightestelementsformthestrongestbonds)Bio-molecules第42頁/共108頁Thetraceelements(Fe,Cu,Mn,Zn,I,Mg)areabsolutelyessentialtolife.第43頁/共108頁Bio-molecules:CompoundsofCarbonCarbon:至少占細胞干重的一半WhyCarbon?versatilebondingcapacityEachCatomcanformverystablesinglebondwith1-4otherCatoms;anddoubleortriplebondsbetweentwoCatoms.CovalentlylinkedCatomscanformdifferentstructures（linear,branched,orcyclic）addingfunctionalgroupsconferringspecificactivitiestothemolecules.第44頁/共108頁Versatilityofcarboninformingcovalentbonds第45頁/共108頁Organiccompounds:Moleculescontainingcovalentlybondingcarbonbackbones;e.g.alcohols,amines,aldehydes(醛),ketones,羧基,巰基,…etcMostbio-moleculesareorganiccompounds.

“C”:tetrahedralarrangementofitsfoursinglebonds.C-Csinglebondshavefreedomofrotation,butnotdoublenortriplebonds.Nootherchemicalelementhasthecapacitytoformmoleculesofsuchwidelydifferentsizes,shapes,withvarietyoffunctionalgroups第46頁/共108頁第47頁/共108頁★Mostbiomoleculescanbeconsideredtobederivedfromhydrocarbons★hydrophilicinteractionsbetweenbiomoleculesHydrocarbons第48頁/共108頁fisherBall-and-stickSpacefillingBio-moleculeshave3-Dstructures第49頁/共108頁Bio-moleculeshave3-DstructuresThespecialfeatureoforganiccompoundsisNOTtheircompositionsbutthewaytheiratomsarecombined(structures,

1820s)Corollary:twosubstancesmayshowthesamechemicalformulabutphysicallyandchemicallydifferentmaterials(differentstructuresandfunctions).第50頁/共108頁Conventionusedforconfiguration第51頁/共108頁Lightabsorbingpigmentinrhodopsinanintegralmembraneprotein第52頁/共108頁Chiral：手性第53頁/共108頁第54頁/共108頁Interactionsbetweenbio-moleculesarestereo-specificBetweenpairsofenantiomers對映(結(jié)構(gòu))體： usuallyonlyoneformisbiologicallyactive. L-aminoacids(S)arefoundinproteins D-glucose(R)isbiologicallyactiveOnlyonechiralformisgeneratedinlivingcellsduetoenzymespecificity(1975NobelPrize)

Incontrast:thetwoenantiomersareusuallysynthesizedinequalamountsinvitrochemicalsynthesis第55頁/共108頁Conventionfromorganicchemistry第56頁/共108頁Chewinggums綠薄荷香菜Twostereoisomersmayhavetotallyoppositebiologicaleffects(e.g.,Chewinggums)第57頁/共108頁Neutralsweet天冬酰苯丙氨酸甲酯

Aspartame,asugarsubstitute;itsstereoisomer,bitter第58頁/共108頁Fourfamilies: Aminoacids；Sugar； Fattyacids；NucleotidesFunctions:Usedtosynthesizelargermolecules；Havespecialbiologicalfunctions；Involvedincomplexreactionpathways；MajorClassesofSmallBio-molecules第59頁/共108頁Fivegeneraltypesofreactionsincells:Oxidation-reduction(氧化－還原反應(yīng))Internalre-arrangements(isomerization,異構(gòu))Cleavage&formationof“C-C”bondsGrouptransfer(親核取代)CondensationBiochemicalReactionSimilartootherchemicalreactions--

brokenandformationofcovalentbonds第60頁/共108頁Oxidation：gainsoxygenorloseshydrogenReduction：losesoxygenorgainshydrogenOxidation-ReductionReactions第61頁/共108頁theintra－molecularshiftofatoms/groups

Internalre-arrangements(isomerization,異構(gòu))

第62頁/共108頁Energy：thecentralthemeinBiochemistry

LivingcellsneedaconstantflowofenergytopreventthemfrombecomingdisorderedLivingcellshaveevolvedsubtlemechanismsforgeneratingandusingenergy第63頁/共108頁AlllifeprocessesconsistofchemicalreactionscatalyzedbyenzymesThereactionsinalivingorganismareknowncollectivelyasmetabolism(代謝）AcquisitionandutilizationofenergySynthesisofmolecules：forcellstructureandfunctioningRemovalofwasteproductsBiochemicalReactioninlife第64頁/共108頁DefinitionofMetabolismThehighlyintegratednetworkofchemicaltransformations.Degradation(decreasingorder,thusenergyreleasing)toprovideenergy,catabolism;Synthesis(increasingorder,thusenergyconsuming)toprovidebuildingmaterials,anabolism.第65頁/共108頁TheRolesofmetabolismExtractenergyandreducingpowerfromtheenvironment(生命體通過光合作用和氧化作用從外界吸收能并釋放廢棄物）Generation(interconversion)ofallthebiomoleculesforalivingorganism(biosynthesis).（伴隨著物質(zhì)和能量代謝，生物分子間通過分解和合成作用發(fā)生互換）第66頁/共108頁Anabolism合成代謝Catabolism

分解代謝能源物質(zhì)中間代謝產(chǎn)物廢棄物第67頁/共108頁GeneralFeaturesofmetabolismlinear,branchedorcircularpathways;Highlyinterconnected

各個途徑相互交接，形成物與能的網(wǎng)絡(luò)化交流系統(tǒng)

Tightlyregulatedtoachievebesteconomy精密調(diào)控機制保證機體最經(jīng)濟的利用物質(zhì)和能量第68頁/共108頁Alllivingorganismsaremadeupofcells, thesmallestunitboththestructural andfunctionaloflivingmatters.Cellsarecapableofself-reproduction.Mostcellsaremicroscopicinsize Eukaryoticcells:5-100mminsize； bacteria:1-2mm;mycoplasma:0.3mmCell:FundamentalUnitofLife第69頁/共108頁Prokaryotic(原核）cells:Lackanucleuse.g.,EubacteriaandarchaeaSimplestructure;Abundant&diverseEukaryotic（真核）cellsPossessanucleusboundedbymembrane,containinggeneticinformationintheformofchromosomesComparison:seeTable2-1,p29LehningerTwocategoryofcells第70頁/共108頁EukaryotesLargerCellvolume；Morecomplicatedcellstructure,withmembrane-boundednucleusandorganelles(細胞器）Energymetabolism:

moreunifiedandpackedinmitochondriaWithcytoskeletonandintracellularmovementCelldividedbymitosisFormmulti-cellularorganisms第71頁/共108頁第72頁/共108頁AdividingE.coli大腸桿菌第73頁/共108頁Saccharomycescerevisiae(baker’syeast)第74頁/共108頁★Permittheconcentrationofreactantandproductmolecules★Makeintricateregulatorymechanismpossible★Cellsofmulti-cellulareukaryotesareabletorespondquicklyandeffectivelytotheintercellularcommunicationAdvantagesfromOrganelles第75頁/共108頁AdvantagesofMulti-cellularorganisms

overunicellularones★Possessarelativelymorestable,controlledenvironmentforcells★Cellshaveadivisionoflaborallowinggreatercomplexityinbothformandfunction★Abletoexploitenvironmentalresourcesmoreeffectively★Theyarehighlyorderedlivingsystems第76頁/共108頁NucleusStorethegeneticinformationcarrier(DNA)SurroundedbyanNenvelop(doublemembraneswithspecializedpores).TheouterlayeriscontinuouswithERmembranesystem.DNAiscondensed螺旋(compressedabout10millionfoldinthelineardimension)inahumanchromosome染色體.第77頁/共108頁Nuclearporesnucleolus第78頁/共108頁DNA被螺旋壓縮(10millionfold

inthelineardimension)后組成染色體第79頁/共108頁第80頁/共108頁EndoplasmicReticulum(ER)內(nèi)質(zhì)網(wǎng)acontinuousmembranesystemconsistoftubes&flattenedsacsforminganenclosedlumenRibosomes(synthesizeproteins)areattachedtothecytoplasmicsurfaceofER,formingtheroughER(RER)structure.

SmoothER(oftentubular)：thesiteforlipidsynthesis；generatestransportvesicles

thatfusewithothermembranesystemsinthecell第81頁/共108頁第82頁/共108頁第83頁/共108頁GolgiApparatus:processandsortproteinsastackofflattenedmembranesacssurroundedbymanysmallvesicles.structurallyandfunctionallyasymmetric,thecissidefaceER；transfaceplasmamembraneProteinsandlipidsmovethroughGolgi體,enteringfromthecissideandexitingfromthetransside.Duringthisprocess,theyareextensivelymodified,e.g.,glycosylated糖基化,sulfated硫酸化,phosphorylated磷酸化,etc.第84頁/共108頁Mitochondria線粒體

Withasmoothoutermembraneandaninfoldedinnermembrane(formingmanycrista突起).Hundredsofenzymescatalyzingtheenergywerecontainedwithininnermembrae,andgeneratetheenergycarrier(ATP)ContainsitsownDNA,RNA,ribosomes核糖體!Itduplicatesitselfwhencelldivides.Playimportantroleincellapoptosis(凋亡）第85頁/共108頁Lysosomes溶酶體第86頁/共108頁M吞噬處理入侵細菌及提呈抗原的機制第87頁/共108頁PlasmamembranePerformsseveralvitalfunctionsforthecell:Transport,whichrequirescarrierandchannelproteinsProvidesmechanicalstrengthandshapetothecellCellcommunicate,responsetoextracellularsignals;specializedfunctionssuchasmusclecontractionandnerveimpulseconduction第88頁/共108頁Plasmamembraneisalipidbilayercomposedoflipidandproteinmolecules第89頁/共108頁Others：Peroxisomes過氧化物酶體Chloroplasts葉綠體Thecytoskeletonsystem……etc第90頁/共108頁Aroughanalogybetweenthethecellandthehumansociety

Nucleus:thehighestadministrativesection.Mitochondriaandchloroplasts:thepowerplant.GolgiApparatus:thepostofficeCytoskeletonsystem:thehighways(transportation)Lysosomes:therecyclingcenterER:thefactory，training&educationcenterPlasmamembrane:theborderlineLikethesociety,thecytoplasmiscrowded,highlyorganized,anddynamic.第91頁/共108頁2004年世界十大科技進展新聞是：

1.“勇氣”&“機遇”號發(fā)現(xiàn)火星有水的證據(jù)第92頁/共108頁第93頁/共108頁ItisNOTanaccidentthatlifearoseinassociationwithwater,sincethissubstancehasseveralunusualpropertiesthatsuitstobe