生物化学教学课件：代谢调节

RegulationofMetabolismRegulationPrinciplesandstrategies1IntegratedNeutrient,EnergyandInformationmetablismPrinciplesandstrategies1IntegratedNeutrient,EnergyandInformationmetablism2CommonPathways3Severalkindsofreactionsvsmanykindsofchemicals氧化还原基团转移水解合成基团脱加异构化Principlesandstrategies4Interchangablebetweencarbonhydrates,lipid,AA,NtKey:G-6-P、Pyr、CH3COCoA,Frmarate

5TCA

istheheartofmetablism6ATP

isthevectorofenerge7Biodegradationprovides:ATP,NADPH,buildingmaterialforbiosynthesisNADPH：dedicatedtosynthesisNADH,FADH2:dedicatedtoproductionofATPGlutaminaseGlutaminesynthetase8Biosynthesisandbiodegradationareseperatedandregulateddifferentially(catalysedbydifferentenzymes)8Biosynthesisandbiodegradationareseperatedandregulateddifferentially(catalysedbydifferentenzymes)9Coordinateofstatuses进食-饥饿循环Well-fed乳糜微粒门静脉9Coordinateofstatuses进食-饥饿循环Earlyfasting肝糖原肝细胞糖酵解维持了禁食早期的血糖水平9Coordinateofstatuses进食-饥饿循环肝糖原Fasting禁食后10-12小时机体主要依赖乳酸、丙酮酸和丙氨酸为原料的肝糖异生作用提供能量。脂肪酯解：脂肪的丙三醇用于葡萄糖合成蛋白质/氨基酸的碳架为葡萄糖合成主要原料肌肉肌肉释放的谷氨氨酰胺为上皮细胞淋巴细胞巨噬细胞所利用脂肪酸为肝外组织细胞提供能量，许多组织优先使用脂肪酸而不是葡萄糖，葡萄糖的合成和尿素合成紧密相关脂肪酸产生酮体，为糖异生提供能量Fatiseasyandslimishard!能量充足的时候，人类能够以远比基础热量需求高的速率消耗食物并储存能量；每天摄入超过热量消耗以外的2份黄油(100卡)将会导致每年体重增加10磅能量不足的时候，葡萄糖水平降低，胰岛素分泌减少，机体减少三碘甲状腺素的形成，降低基础代谢（减少25%）；1小时长跑（5-6miles）=2块方糖Obesity（肥胖）人体大部分脂肪直接来源于食物，只有一小部分在肝脏合成后运输到脂肪组织或者由脂肪细胞合成Dieting：低糖生酮饮食方案Exercise：消耗肌糖、原肝糖原和脂肪保证血糖浓度长时间大强度运动中，运动前肌糖原储量决定了运动力枯竭的时间，是冲刺阶段的决定因素血糖，糖原和运动糖代谢和运动的关系无氧运动前必须有足够的肌糖原储量肝糖原，血糖，肌糖原，糖异生之间的关系糖原和运动的关系长期运动训练使机体组织中糖原增多

葡萄糖酵解途径丙酮酸有氧无氧H2O，CO2乳酸糖异生途径乳酸、氨基酸、甘油糖原肝糖原分解糖原合成酶磷酸戊糖途径

核糖

+NADPH+H+淀粉消化与吸收ATPPregnancy：葡萄糖和氨基酸消耗的增加Cancer：葡萄糖酵解为肿瘤供能糖代谢在正常细胞和肿瘤细胞中的差异Warburgeffect肿瘤细胞依赖糖酵解通路产能的现象缺乏氧气对依赖氧化磷酸化产能的细胞来说是致命的糖代谢在正常细胞及干细胞中的差异低氧条件培养加强了干细胞的活力Liverdiseases：尿素循环障碍，高血氨KidneyDiseases：氨基酸代谢氨基酸浓度增加，氮终产物储积Alcohol：产生乙醛和过多的NADH,抑制糖异生、抑制脂肪酸氧化、抑制三羧酸循环EnviromentalligandsSignaltransductionLevelofenzymesExpressionregulationvsProteindegradationMolecularInsighttoMetablismRegulationCharacteristicsofRegulatoryEnzymes!Irreversiblestep!Requiresenergy!OftenresultsinaphosphorylatedcompoundThemostresponsiveregulationofmetablismtakesplaceatfirstreaction,whichisusuallyirreversibleandcatalyzedbyanallostericenzyme.Rate-limitingstepCommittedstep-EarlystepuniquetoapathwayTypesofRegulatoryMechanismsNon-covalentinteractionsCovalentmodificationsChangesinabundanceoftheenzymeAllostericRegulationBindingofallostericeffectorsatallostericsitesaffectcatalyticefficiencyoftheenzyme,AllostericActivators:DecreaseKm;IncreasesVmaxSubstratesofpathwaysFeed-forwardactivatorsEndproductsofpathwaysFeedbackinhibitionIndicatorsofEnergyStatus&Conc.ATP/ADP/AMPNAD/NADHacetylCoA

Enzymemultiplicity（多样性）AllostericRegulation（变构调节）Isozymes（同工酶）EndproductfeedbackinhibitionConcertedinhibition（协调抑制）SequentialfeedbackInhibition（顺序反馈抑制）AminoAcidBiosynthesisIsunderAllostericRegulationTypesofRegulatoryMechanismsCovalentmodificationsChangesinabundanceoftheenzymeTypesofRegulatoryMechanismsNon-covalentinteractionsCovalentmodificationsChangesinabundanceofenzymeDegradationofEnzymes---ubiquitin-mediatedInduciblevsConstitutiveEnzymesInductioniscausedbyincreasesinrateofgenetranscription.HormonesactivatetranscriptionalfactorsIncreasesynthesisofspecificmRNAIncreasesynthesisofspecificenzymesUbiquitinpathwayE1-S-UbE2-S-UbE3substratesUbMono-ubiquitinationChangeproteinconformation,Localization,interactionPolyubiquitinationUbUbUbUbsubstratesProteosomeDegradationE1-Ubactivatingenzyme(Uba)UsesATPAMP+PPitoformthioesterbondbetweenitssulfhydrylgroupandtheterminalcarboxylategroupofUBE2-Ubconjugatingenzyme(Ubc):AcceptsactivatedUBE3-UbLigase:CatalyzestransferofUBfromE2to