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1、GlycolysisCarbohydrateMetabolism 2To teach is not to fill a vase but to light a fire一 、糖酵解的研究历史解释发酵现象的人1822-1895 Louis Paster发酵是由微生物引起的发现酵解本质的人1897 榨酵母汁 蔗糖Hans Buchner 和 Edward Buchner发酵并不需要整个完整细胞参与Eduard BuchnerEmbden, Meyerhof, Parnas 等人贡献最多, 故糖酵解过程也叫Embden-Meyerhof-Parnas途径, 简称EMP途径.贡献最多的人Otto Fr
2、itz Meyerhof二、糖酵解过程概述1、碳骨架的变化:6 C糖(葡萄糖 )2个3 C糖(丙酮酸)2 乳酸(酵解)2 乙醇 2 CO22、能量的变化(1)带有极性,不易随便出入细胞(2)被酶识别,与酶结合(3)传递能量,保存能量3、糖酵解中间产物都是磷酸化合物(发酵)三、糖酵解和酒精发酵的全过程图解HATPADPATPADP2 Pi2ATP2ADP葡萄糖葡萄糖-6-P果糖-6-P果糖-1,6-二磷酸甘油醛-3-磷酸二羟丙酮磷酸1,3-二磷酸甘油酸3-磷酸甘油酸2-磷酸甘油酸磷酸烯醇式丙酮酸烯醇式丙酮酸丙酮酸乳酸1112123456789102 H2ATP2ADP2H2O2 NAD2 NAD
3、HHCHO| CH3 2 CO2 13乙醛CH2OH | CH3 乙醇2 H14准备阶段-消耗ATP葡萄糖ATP葡萄糖-6-磷酸果糖-6-磷酸ATP1,6-二磷酸果糖甘油醛-3-磷酸二羟丙酮磷酸四、糖酵解第一阶段的反应机制(一)葡萄糖的磷酸化 Phosphorylation of GlucoseOHOHOHOHHO2-O3POCH2HHHOHOHOHOHHOHOCH2 HHHATPADPMg2+己糖激酶葡萄糖 G6-磷酸葡萄糖 G-6-P己糖激酶:(1)专一性不强 (mannose/fructose)(2)受产物葡萄糖-6-磷酸和ADP抑制(变构抑制剂)葡萄糖激酶(肝脏):(1)只作用于葡萄糖
4、(2)对葡萄糖的Km较大(与己糖激酶相比) 葡萄糖 较高时作用,G6P促进糖原合成(3)不受产物葡萄糖-6-磷酸的抑制意义:|活化葡萄糖;磷酸化后葡萄糖无法出细胞。|是细胞的保糖机制。葡萄糖与已糖激酶结合时的构象变化结合前结合后(二)G-6-P异构化成果糖-6-磷酸 Conversion of Glucose-6-Phosphate to Fructose-6-PhosphateOHOHOHOHHO2-O3POCH2HHH.OOHHHOHHOH CH2OH2-O3POCH2HCO| HCOH|HOCH | HCOH| HCOH| CH2OPO32- CH2OH| CO|HOCH | HCOH|
5、 HCOH| CH2OPO32-Glucose 6-phosphate (open-chain form) 6-磷酸葡萄糖G-6-PFructose 6-phosphate (open-chain form) 6-磷酸果糖F-6-P磷酸己糖异构酶磷酸葡萄糖异构酶(磷酸果糖异构酶)异构时开环。 可逆反应使羰基从C1位转移到C2位上,C1位上-OH游离,为第二次磷酸化打基础磷酸己糖异构酶催化机制(三)F6P形成果糖-1,6-二磷酸 Phosphorylation of F6P to Fructose-1,6-BisphosphateOOHHHOHHCH2OHOH2-O3POCH2OOHHHOHH
6、CH2OPO32-OH2-O3POCH26-磷酸果糖激酶-1ATPADP6-磷酸果糖F-6-P1,6-二磷酸果糖F-1,6-BP 磷酸果糖激酶-1ATP抑制 ATP既是底物又是变构抑制剂。怎么实现?结合部位不同。AMP去除ATP抑制作用 通过 AMP/ATP 比值调节酶活性.H+过高抑制酶活性 避免酸中毒。 (四)F-1,6-BP裂解 Cleavage of Fructose-1,6-Bisphosphate HCO | HCOH| CH2OPO323-磷酸甘油醛 CH2OPO32-| CO| CH2OH磷酸二羟丙酮 CH2OPO32-| CO|HOCH | HCOH| HCOH| CH2OP
7、O32-+醛缩酶该反应 在标准状况下是吸能反应 在生理条件下是放能反应,两个三碳糖不断被消耗高等植物组织, 脊椎动物组织的醛缩酶不需要二价离子Aldolase- type许多微生物的(细菌、酵母、真菌及藻类)醛缩酶含Zn2+Aldolase- typeX HB CH2OPO32-| CO| HCOH CH2OPO32-| CO|HOCH | HCOH| HCOH| CH2OPO32-X:BX:B CH2OPO32-| C=O| CH2OHDihydroxyacetone phosphate HCO | HCOH| CH2OPO32Glyceraldehyde 3-phosphate| Fruc
8、tose 1,6-bisphosphate is the aldol substrate.| Aldolases have an electron-withdrawing group (X) that polarizes the C-2 carbonyl group of the substrate. One class of aldolase (from plants and animals) uses the amino group of a lysine residue at the active site, and the other (from fungi, algae, and s
9、ome microorganisms) uses Zn2+ for this purpose. | A basic residue (designated B: ) removes a proton from the C-4 hydroxyl group of the substrate.Mechanism of aldol醇醛醇醛 cleavage catalyzed by aldolases(五) 两个磷酸丙糖的互变 Interconversion of the Triose Phosphates CH2OPO32-| CO| CH2OH HCO | HCOH| CH2OPO32甘油醛-3
10、-磷酸磷酸二羟丙酮丙糖磷酸异构酶丙糖磷酸异构酶 8股折叠链环抱成核心; 每条折叠外围有螺旋; 由无规卷曲相连.生理状况下磷酸甘油醛不断被消耗, 磷酸二羟丙酮不断地被异构化. 该反应平衡点时:Enediolate intermediateHN NCH2 O OH C | CH2 H2C | H OH1C | 2CO | 3CH2OPO32Glu-165His-95HN NCH2 O O C | CH2 H2C | H H | OH1C | 2CO | 3CH2OPO32Glu-165His-95Enediol intermediateH:NN:CH2 O OH C | CH2 H2C | H O
11、 1C | 2COH | 3CH2OPO32Glu-165His-95HCH2 H O 1C | 2COH | 3CH2OPO32 O O C | CH2 H2C | HN NGlu-165His-95HN NCH2 O O C | CH2 H2C | H O 1C | H2COH | 3CH2OPO32Glu-165His-95Enediolate intermediate丙糖磷酸异构酶催化机制by radioisotopic tracer studies. Carbons 1,2, and 3 of one glyceraldehyde 3-phosphate are derived fr
12、om carbons 4, 5, and 6 of glucose Carbons 1, 2, and 3 of the second glyceraldehyde 3-phosphate (converted from dihydroxyacetone phosphate) originate as carbons 3, 2, and 1 of glucose. The fate of the individual carbon atoms of a molecule of glucoseGlyceraldehyde 3-phosphate HCO | HCOH| CH2OPO32456Fr
13、uctose-1,6-biphosphate CH2OPO32-| CO|HOCH | HCOH| HCOH| CH2OPO32-456123Fructose CH2OH | CO|HOCH | HCOH| HCOH| CH2OH 123456 CH2OPO32-| C=O| CH2OH HCO | HCOH| CH2OPO32Dihydroxyacetone phosphatetriose phosphate isomeraseGlyceraldehyde 3-phosphate321123aldolase放能阶段-产生ATP和NADH甘油醛-3-磷酸1,3-二磷酸甘油酸3-磷酸甘油酸2-磷
14、酸甘油酸磷酸烯醇式丙酮酸丙酮酸NAD+PiNADHADPATPADPATP五、糖酵解第二阶段放能阶段的反应机制(六)甘油醛-3-磷酸的氧化 Oxidation of Glyceraldehyde-3-Phosphate to 1,3-Bisphosphoglycerate HCO | HCOH| CH2OPO323-磷酸甘油醛 OCOPO32 | HCOH| CH2OPO321,3-二磷酸甘油酸NAD+ + PiNADH + H+甘油醛-3-磷酸脱氢酶甘油醛-3-磷酸脱氢酶催化机制。甘油醛-3-磷酸脱氢酶活性中心含游离-SH,碘乙酸会抑制该酶的活性不可逆。砷酸盐与磷酸结构相似,替代磷酸形成1-
15、砷酸-3-磷酸甘油酸,进一步水解为3-磷酸甘油酸,无法形成形成高能磷酸键解偶联剂。 OCOAsO32 | HCOH| CH2OPO321-砷酸-3-磷酸甘油酸(七)高能磷酸基团的转移 Transfer of Phosphate from 1,3- BPG to ADP OCOPO32 | HCOH| CH2OPO32 OCO | HCOH| CH2OPO321,3-二磷酸甘油酸3-磷酸甘油酸ADPATP磷酸甘油酸激酶糖酵解中第一个产生ATP的反应底物水平磷酸化磷酸甘油酸激酶催化反应的机理磷酸甘油酸激酶催化反应的机理Mechanism of the PGK reaction.(八) 3-磷酸甘油
16、酸转变为2-磷酸甘油酸 Converston of 3-Phosphoglycerate to 2-PG OCO | HCOH| CH2OPO323-磷酸甘油酸 OCO | HCOPO32| CH2OH2-磷酸甘油酸磷酸甘油酸变位酶 磷酸甘油酸变位酶催化机制(九)磷酸烯醇式丙酮酸生成 Dehydration of 2-Phosphoglycerate to Phosphoenolpyruvate 2-磷酸甘油酸 OCO | COPO32| CH2磷酸烯醇式丙酮酸烯醇化酶H2OH2O OCO | HCOPO32| CH2OH烯醇化酶与2价离子结合后才有活性氟化物抑制剂Step 9. 烯醇化酶烯醇
17、化酶(2-磷酸甘油酸脱水酶磷酸甘油酸脱水酶)Enolase (2-phosphoglycerate dehydratase) reactionReaction mechanismof enolase.负碳中间物负碳中间物酶分子的活性部位酶分子的活性部位慢慢快快(十)丙酮酸及ATP的产生 Transfer of the Phosphate Group from Phosphoenolpyruvate to ADP OCO | COPO32| CH2磷酸烯醇式丙酮酸 OCO | COH | CH2烯醇式丙酮酸 OCO | CO| CH3丙酮酸丙酮酸激酶Mg2+糖酵解中第二个产生ATP的反应底物水平
18、磷酸化丙酮酸激酶催化机制ADPATP反 应ATP葡萄糖6-磷酸葡萄糖16-磷酸果糖1,6-二磷酸果糖11,3-二磷酸甘油酸3-磷酸甘油酸21磷酸烯醇式丙酮酸丙 酮 酸21糖酵解过程中ATP的消耗和产生葡萄糖2Pi2ADP2NAD 2 丙酮酸2ATP2NADH2H2H2O六、由葡萄糖转变为丙酮酸的能量变化七、丙酮酸的去路 COO| CO| CH3 COO| CHOH| CH3 OH| CH2| CH3 SCoA| CO| CH3ADP + PiATPO24CO2O2CO2CO2OHOHOHOHHOCH2OHHHHATPGlycolysis丙酮酸有氧情况缺氧情况三羧酸循环(动物 植物等)乙醛酸循环
19、(植物)乳酸发酵(动物)乙醇发酵(植物 酵母等)乳酸脱氢酶( lactate dehydrogenase ,LDH)LDH1(H4)分布于心肌(H)LDH2(H3M)LDH3(H2M2)LDH4(HM3)LDH5(M4)分布于骨骼肌(M)LDH催化丙酮酸还原成乳酸, 乳酸脱氢氧化成丙酮酸.心脏、脑、肾LDH1含量高(Km高)生成丙酮酸骨骼肌中LDH5含量高(Km低)生成乳酸HHis195Arg171NAD+(Oxidized coenzyme)L-Lactate(Reduced substrate)COO |CHOH |CH3COO |CO |CH3NADH, H+NAD+lactate de
20、hydrogenaseGlucose + 2 Pi2- + 2 ADP3- 2 Lactate- + 2 ATP4- + 2 H2O 乙醇生成乙醇生成(发酵发酵)Glucose + 2 Pi2- + 2 ADP3- + 2 H+ 2 Ethanol + 2 CO2 + 2 ATP4- + 2 H2O 运动员在进行不同项目运动时机体的供能方式 注:摘自2001年高考理科综合试卷第I卷第2题。八、糖酵解作用的调节| 限速反应/关键反应 在物质代谢整个反应链中,某一步反应速度决定整个反应链的速度,这一步反应称限速反应/关键反应。催化该反应的酶称限速酶/关键酶。| 糖酵解途径限速酶:己糖激酶、磷酸果糖
21、激酶、丙酮酸激酶。1. 磷酸果糖激酶-1是最重要的调节酶(变构酶) 抑制剂: ATP、柠檬酸 激活剂: AMP、ADP、 6-磷酸果糖、2, 6-二磷 酸果糖 (果糖-6-磷酸有加速果糖-2,6-二磷酸合成的作用,还有抑制该化合物被水解的作用。高浓度果糖-6-磷酸可导致高浓度果糖-2,6-二磷酸,进一步激活果糖磷酸激酶-1) 位于一条多肽链上的Ser-OH磷酸化, 水解活性激活, 激酶活性抑制。2. 己糖激酶 乙酰CoA和脂肪酸对酶有抑制作用, 产物葡萄糖-6-磷酸是变构抑制剂。糖酵解最关键酶是磷酸果糖激酶,不是己糖激酶3. 丙酮酸激酶 变构抑制剂: ATP、丙氨酸、乙酰CoA、脂肪酸;变构激
22、活剂: 1,6-二磷酸果糖共价修饰 磷酸化后失活OOHHHOHH CH2OH OPO2-32-O3POCH2果糖果糖-2,6-二磷酸对磷酸果糖激酶的激活作用二磷酸对磷酸果糖激酶的激活作用ATPADPPiH2O-D-Fructose 2,6-bisphosphate-D-Fructose 6-bisphosphatePFK-2Fructose 2,6- bisphosphataseOPO32-O-O2P3OH2CHOHCH2OHHHOH高高浓度浓度ATP低低浓度浓度ATP0果糖果糖-6-磷酸浓度磷酸浓度反反应应速速度度丙酮酸激酶催化活性控制关系图丙酮酸激酶催化活性控制关系图磷酸化的丙酮酸激酶磷酸
23、化的丙酮酸激酶(低活性)(低活性)去磷酸化的丙酮酸激酶去磷酸化的丙酮酸激酶(高活性)(高活性)H2OPiATPADP果糖果糖-1,6-二磷酸二磷酸ATP丙氨酸丙氨酸+低血糖低血糖Pi+九、其他六碳糖进入糖酵解的途径 Fructose Galactose MannoseConversion of fructose into two molecules of glyceraldehyde 3-phosphate.A. Fructose is Converted to Glyceraldehyde 3-PhosphateGlyceraldehyde 3-phosphate HCO | HCOH| C
24、H2OPO32Fructose-1-phosphate CH2OPO32-| CO|HOCH | HCOH| HCOH| CH2OH Fructose CH2OH | CO|HOCH | HCOH| HCOH| CH2OH CH2OPO32-| CO| CH2OH HCO | HCOH| CH2OPO32Dihydroxyacetone phosphatetriose phosphate isomeraseGlyceraldehyde 3-phosphatealdolase CHO | HCOH| CH2OHGlyceraldehydetriose kinaseATP ADPFructokin
25、aseATP ADPB. Galactose Is Converted to Glucose 1-Phosphate| The disaccharide lactose, present in milk, is a major source of energy for nursing mammals. | In newborns, intestinal肠内的肠内的lactase catalyzes the hydrolysis of lactose to its components, glucose and galactose, both of which are absorbed from
26、 the intestine and transported in the bloodstream.PhosphoglucomutaseGalactokinaseATP ADPGalactoseGalactose-1-phosphateUDP-glucoseUDP-galactoseGlucose-1-phosphateGlucose-6-phosphateGalactose-1-phosphateuridylyltransferase| Conversion of galactose to glucose 6-phosphate. |The metabolic intermediate UD
27、P-glucose is recycled in the process. |The overall stoichiometry for the pathway is galactose +ATP glucose 6-phosphate + ADPUDP-glucose 4-epimeraseGalactosemia半乳糖血半乳糖血(症症)|Infants fed an exclusive diet of milk rely on galactose metabolism for about 20% of their caloric intake.|In the most common for
28、m of the genetic disorder galactosemia (the inability to properly metabolize galactose), infants are deficient in galactose 1-phosphate uridylyltransferase. T Deficiency of galactose-1- phosphate uridylytransferase.T galactose-1-phosphate accumulates T Leads to liver damageT Can be treated with gala
29、ctose free diet.PhosphoglucomutaseGalactokinaseATP ADPGalactoseGalactose-1-phosphateUDP-glucoseUDP-galactoseGlucose-1-phosphateGlucose-6-phosphateGalactose-1-phosphateuridylyltransferaseC. Mannose Is Converted to Fructose 6-Phosphateu Mannose甘露糖甘露糖can be phosphorylated to mannose-6-phosphate by hexo
30、kinase and then converted to fructose-6-phosphate by phosphomannose isomerase.PO32PhosphomanoseisomeraseHexokinaseATPADP2O3PCH2OHOOH2CHO HHOHOHGlucoseG-6-PF-6-P1,6-FBPG3PDHAPG3P1,3-BPG3-PG2-PGPEPPyruvate1,3-BPG3-PG2-PGPEPPyruvateGalactose-1-PUDP-GalUDP-GlucoseGlucose-1-PMannoseMannose-6-PFructose6-PD-glyceraldehydealdolaseTriosekinaseGalactoseFructoseThank you