生物化學(xué)教學(xué)課件：代謝調(diào)節(jié)

RegulationofMetabolismRegulationPrinciplesandstrategies1IntegratedNeutrient,EnergyandInformationmetablismPrinciplesandstrategies1IntegratedNeutrient,EnergyandInformationmetablism2CommonPathways3Severalkindsofreactionsvsmanykindsofchemicals氧化還原基團(tuán)轉(zhuǎn)移水解合成基團(tuán)脫加異構(gòu)化Principlesandstrategies4Interchangablebetweencarbonhydrates,lipid,AA,NtKey:G-6-P、Pyr、CH3COCoA,Frmarate

5TCA

istheheartofmetablism6ATP

isthevectorofenerge7Biodegradationprovides:ATP,NADPH,buildingmaterialforbiosynthesisNADPH：dedicatedtosynthesisNADH,FADH2:dedicatedtoproductionofATPGlutaminaseGlutaminesynthetase8Biosynthesisandbiodegradationareseperatedandregulateddifferentially(catalysedbydifferentenzymes)8Biosynthesisandbiodegradationareseperatedandregulateddifferentially(catalysedbydifferentenzymes)9Coordinateofstatuses進(jìn)食-饑餓循環(huán)Well-fed乳糜微粒門靜脈9Coordinateofstatuses進(jìn)食-饑餓循環(huán)Earlyfasting肝糖原肝細(xì)胞糖酵解維持了禁食早期的血糖水平9Coordinateofstatuses進(jìn)食-饑餓循環(huán)肝糖原Fasting禁食后10-12小時(shí)機(jī)體主要依賴乳酸、丙酮酸和丙氨酸為原料的肝糖異生作用提供能量。脂肪酯解：脂肪的丙三醇用于葡萄糖合成蛋白質(zhì)/氨基酸的碳架為葡萄糖合成主要原料肌肉肌肉釋放的谷氨氨酰胺為上皮細(xì)胞淋巴細(xì)胞巨噬細(xì)胞所利用脂肪酸為肝外組織細(xì)胞提供能量，許多組織優(yōu)先使用脂肪酸而不是葡萄糖，葡萄糖的合成和尿素合成緊密相關(guān)脂肪酸產(chǎn)生酮體，為糖異生提供能量Fatiseasyandslimishard!能量充足的時(shí)候，人類能夠以遠(yuǎn)比基礎(chǔ)熱量需求高的速率消耗食物并儲(chǔ)存能量；每天攝入超過(guò)熱量消耗以外的2份黃油(100卡)將會(huì)導(dǎo)致每年體重增加10磅能量不足的時(shí)候，葡萄糖水平降低，胰島素分泌減少，機(jī)體減少三碘甲狀腺素的形成，降低基礎(chǔ)代謝（減少25%）；1小時(shí)長(zhǎng)跑（5-6miles）=2塊方糖Obesity（肥胖）人體大部分脂肪直接來(lái)源于食物，只有一小部分在肝臟合成后運(yùn)輸?shù)街窘M織或者由脂肪細(xì)胞合成Dieting：低糖生酮飲食方案Exercise：消耗肌糖、原肝糖原和脂肪保證血糖濃度長(zhǎng)時(shí)間大強(qiáng)度運(yùn)動(dòng)中，運(yùn)動(dòng)前肌糖原儲(chǔ)量決定了運(yùn)動(dòng)力枯竭的時(shí)間，是沖刺階段的決定因素血糖，糖原和運(yùn)動(dòng)糖代謝和運(yùn)動(dòng)的關(guān)系無(wú)氧運(yùn)動(dòng)前必須有足夠的肌糖原儲(chǔ)量肝糖原，血糖，肌糖原，糖異生之間的關(guān)系糖原和運(yùn)動(dòng)的關(guān)系長(zhǎng)期運(yùn)動(dòng)訓(xùn)練使機(jī)體組織中糖原增多

葡萄糖酵解途徑丙酮酸有氧無(wú)氧H2O，CO2乳酸糖異生途徑乳酸、氨基酸、甘油糖原肝糖原分解糖原合成酶磷酸戊糖途徑

核糖

+NADPH+H+淀粉消化與吸收ATPPregnancy：葡萄糖和氨基酸消耗的增加Cancer：葡萄糖酵解為腫瘤供能糖代謝在正常細(xì)胞和腫瘤細(xì)胞中的差異Warburgeffect腫瘤細(xì)胞依賴糖酵解通路產(chǎn)能的現(xiàn)象缺乏氧氣對(duì)依賴氧化磷酸化產(chǎn)能的細(xì)胞來(lái)說(shuō)是致命的糖代謝在正常細(xì)胞及干細(xì)胞中的差異低氧條件培養(yǎng)加強(qiáng)了干細(xì)胞的活力Liverdiseases：尿素循環(huán)障礙，高血氨KidneyDiseases：氨基酸代謝氨基酸濃度增加，氮終產(chǎn)物儲(chǔ)積Alcohol：產(chǎn)生乙醛和過(guò)多的NADH,抑制糖異生、抑制脂肪酸氧化、抑制三羧酸循環(huán)EnviromentalligandsSignaltransductionLevelofenzymesExpressionregulationvsProteindegradationMolecularInsighttoMetablismRegulationCharacteristicsofRegulatoryEnzymes!Irreversiblestep!Requiresenergy!OftenresultsinaphosphorylatedcompoundThemostresponsiveregulationofmetablismtakesplaceatfirstreaction,whichisusuallyirreversibleandcatalyzedbyanallostericenzyme.Rate-limitingstepCommittedstep-EarlystepuniquetoapathwayTypesofRegulatoryMechanismsNon-covalentinteractionsCovalentmodificationsChangesinabundanceoftheenzymeAllostericRegulationBindingofallostericeffectorsatallostericsitesaffectcatalyticefficiencyoftheenzyme,AllostericActivators:DecreaseKm;IncreasesVmaxSubstratesofpathwaysFeed-forwardactivatorsEndproductsofpathwaysFeedbackinhibitionIndicatorsofEnergyStatus&Conc.ATP/ADP/AMPNAD/NADHacetylCoA

Enzymemultiplicity（多樣性）AllostericRegulation（變構(gòu)調(diào)節(jié)）Isozymes（同工酶）EndproductfeedbackinhibitionConcertedinhibition（協(xié)調(diào)抑制）SequentialfeedbackInhibition（順序反饋抑制）AminoAcidBiosynthesisIsunderAllostericRegulationTypesofRegulatoryMechanismsCovalentmodificationsChangesinabundanceoftheenzymeTypesofRegulatoryMechanismsNon-covalentinteractionsCovalentmodificationsChangesinabundanceofenzymeDegradationofEnzymes---ubiquitin-mediatedInduciblevsConstitutiveEnzymesInductioniscausedbyincreasesinrateofgenetranscription.HormonesactivatetranscriptionalfactorsIncreasesynthesisofspecificmRNAIncreasesynthesisofspecificenzymesUbiquitinpathwayE1-S-UbE2-S-UbE3substratesUbMono-ubiquitinationChangeproteinconformation,Localization,interactionPolyubiquitinationUbUbUbUbsubstratesProteosomeDegradationE1-Ubactivatingenzyme(Uba)UsesATPAMP+PPitoformthioesterbondbetweenitssulfhydrylgroupandtheterminalcarboxylategroupofUBE2-Ubconjugatingenzyme(Ubc):AcceptsactivatedUBE3-UbLigase:CatalyzestransferofUBfromE2to