第4章-糖代谢

1、Part Metabolism and its RegulationMetabolism-Overview Metabolism is a feature of life Metabolism consists of catabolism & anabolism Catabolism: degradative pathways Usually energy-yielding! Anabolism: biosynthetic pathways energy-requiring! Basic procedure of metabolism Digestion & absorptio

2、n Intermediary metabolism ExcretionOutline Carbohydrate Metabolism Lipid Metabolism Biological Oxidation Amino Acid Metabolism Nucleotide Metabolism Integration of MetabolismChapter 4Metabolism of Carbohydrates Chemistry of Carbohydrate Carbohydrates Classification Momosaccharide Oligosaccharide Pol

3、ysaccharide Glycoconjugate2. Oligosaccharide Common disaccharide麦芽糖(maltose)：GluGlu蔗糖(sucrose)：GluF乳糖(lactose)：GluGal 3. Polysaccharide 淀粉(starch) 纤维素(cellulose) 糖原(glycogen)StarchGlycogenCellulose 4. Glycoconjugate 糖与非糖物质的结合物 常见的结合糖 糖蛋白(glycoprotein) 糖脂 (glycolipid)4.1 Introduction Functions of car

4、bohydrate Digestion & Absorption Overview of carbohydrate metabolism 1. Functions of Carbohydrate Providing energy Providing carbon Acting as structural components Special functions 2. Digestion & Absorption Digestion Location： small intestine Procedure Products：monosaccharide(Glu, Gal, F) A

5、bsorption Location： small intestine Type：monosaccharide Mechanism：active absorption淀 粉麦芽糖 麦芽三糖 -临界糊精 异麦芽糖 40% 25% 30% 5% 葡萄糖-葡萄糖苷酶-临界糊精酶 -淀粉酶 蔗糖G + F 乳糖G + Gal3. Overview of Carbohydrate Metabolism Glucose transporter(GLUT)葡萄糖葡萄糖糖原H2O CO2乳酸磷酸戊糖途径 合成 分解糖异生有氧氧化无氧分解8.2 Anaerobic Catabolism of Carbohydr

6、ates 1. Procedure of Glycolysis Glycolysis: Glucose Lactate + ATP anaerobic condition Two Phases G2 pyruvate pyruvatelactate First phase：GPyruvateReaction 1phosphorylation of glucose激 酶(kinase) ATP + 底物 底物-P + ADP (高能磷酸化合物) 特点 催化不可逆反应 需要Mg2+ 受激素调控己糖激酶和葡萄糖激酶 己糖激酶(hexokinase, HK) 葡萄糖激酶(glucosekinase,

7、GK) 部位 专一性 G的亲和力 HK 各组织 低 高 GK 肝 高 低Reaction 2Rx3: 6-phosphofructokinase-1(PFK-1)Rx 4: AldolaseC6 cleaves to 2 C3s (DHAP, Gly-3-P) Rx 5: Triose Phosphate IsomeraseDHAP converted to Gly-3-P Rx 6: Gly-3-DehydrogenaseGly-3P is oxidized to 1,3-BPG Reaction 7底物水平磷酸化(substrate-level phosphorylation) 定义： A

8、DP/GDP 磷酸化为ATP/GTP与底物 的氧化作用直接偶联。 机制：底物分子内部能量重新分布，形成 高能键 区别于氧化磷酸化Rx 8: Phosphoglycerate MutasePhosphoryl group from C-3 to C-2 Rx 9: Enolase2-PG to PEP Rx10: Pyruvate KinaseSecond Phase：PyruvateLactateFeatures of Glycolysis Location-cytosol Energy-yielding ：2ATP Key enzymes：HK, PFK-1, pyruvate kinase

9、 The fate of NADH+H+ anaerobic is oxidized by LDH to provide NAD+ aerobicelectron transfer chain The fate of pyruvate anaerobic LDH makes lactate aerobic TCA 2. Regulation of Glycolysis Rate-limiting enzymes HK PFK-1 Pyruvate kinase Pattern of regulation Allosteric regulation Covalent modificationPF

10、K-1 Allosteric regulation ActivatorsAMP, ADP, F-1,6-2P, F-2,6-2P InhibitorsATP，citrate PFK-2= PFK-2 + FBP-2 Covalent modification of PFK-2 Glucagon+PKAPFK-2F-2,6-2P Glycolysis Pyruvate Kinase 变构调节：激活剂F-1,6-2P; 抑制剂ATP, Ala 共价修饰调节丙酮酸激酶 (+)丙酮酸激酶-P (-)蛋白激酶磷蛋白磷酸酶胰高+HK & GK Allosteric Inhibitors HK: G

11、-6-P GK: acyl-CoA Aim of regulation ATP Glycolysis ATP Glycolysis 3. 糖酵解的生理功能 迅速提供能量，对肌肉收缩特别重要 是一些细胞在氧供应正常情况下的重要供能途径 成熟红细胞 代谢活跃的细胞：神经、白细胞、骨髓 4.3 Aerobic Oxidation of Carbohydrate 概念：葡萄糖在有氧条件下，彻底氧化成H2O和CO2，并释放出大量能量的过程。 是糖氧化的主要方式 1. Procedure of Aerobic Oxidation Three phases Glycolytic pathway：G2 Pyr

12、uvate cytosol Pyruvateacetyl CoA： mitochondria TCA & oxidative phosphorylation：mitochondria (1) Oxidative Decarboxylation of PyruvateHSCoA CoA辅酶A丙酮酸脱氢酶复合体 E1 ：丙酮酸脱氢酶 TPP E2 ：转乙酰化酶 硫辛酸 E3 ：二氢硫辛酰胺脱氢酶 FAD、NAD+(2)Tricarboxylic Acid Cycle(TCA cycle）Citrate cycle , Krebs cycleReaction 1 : Citrate Synt

13、haseRx 2: AconitaseIsomerization of Citrate to Isocitrate Rx3: The First Oxidative DecarboxylationRx4: Second Oxidative Decarboxylation Rx 5: Succinyl-CoA SynthetaseA substrate-level phosphorylation Reaction 6An oxidation involving FADRx 7: FumaraseHydration across the double bond Rx 8: Malate Dehyd

14、rogenaseAn NAD+-dependent oxidation 三羧酸循环三羧酸循环草酰乙酸草酰乙酸柠檬酸柠檬酸异柠檬酸异柠檬酸a a- -酮戊二酸酮戊二酸琥珀酸琥珀酸辅酶辅酶A A琥珀酸琥珀酸延胡索酸延胡索酸苹果酸苹果酸乙酰辅酶乙酰辅酶A AFeatures of TCA Cycle Location：mitochondria 4 dehydrogenation：3 NADH+H+ ， 1FADH2 2 decarboxylation： 2CO2 1 substrate-level phosphorylation：1GTP Energy-yielding: 12ATP 3X 3ATP

15、 + 1X 2ATP + 1ATP=12ATP Irreversible:citrate synthase, isocitrate dehydrogenase, - ketoglutarate dehydrogenase complex Intermediates acts as catalystsTrue or False? 通过TCA循环可以生成柠檬酸/琥珀酸/草酰乙酸( ) 柠檬酸/琥珀酸/草酰乙酸在TCA循环中被直接氧化( ) TCA cycle 的总反应三羧酸循环的生理意义三羧酸循环的生理意义 是三大营养素的最终代谢通路 是糖、脂肪、氨基酸代谢联系的枢纽 糖脂肪 AATCA的中间产物

16、草酰乙酸糖 葡萄糖非必需AA(Asp, Glu) 提供生物合成的前体 为呼吸链提供还原当量(NADH+H+, FADH2) 2. Features of Aerobic Oxidation Location：cytosolmitochondria 7 key enzymes Providing energy 1st phase 2nd phase 3rd phase22X3(2X2) + 2X3 + 2X12 =38/36ATP 3. Regulation of Aerobic Oxidation Regulation of glycolysis Regulation of pyruvate

17、dehydrogenase complex Regulation of TCA cycleRegulation of Pyruvate Dehydrogenase Complex Allosteric regulation ActivatorsAMP, ADP, NAD+ Inhibitorsacetyl CoA、NADH+H+、ATP Covalent modification三羧酸循环的调节 异柠檬酸脱氢酶和-酮戊二酸脱氢酶 激活剂 抑制剂异柠 NAD+, Ca2+,ADP NADH ,ATP-酮 NAD+ ,Ca2+ NADH ,ATP,琥珀酰CoA 氧化磷酸化的速率Ca2+Why re

18、gulate aerobic oxidation? To meet needs of energy ATP aerobic oxidation ATP aerobic oxidation 思考题 比较糖酵解和有氧氧化的异同（ 底物、产物、条件、部位、基本过程、产能、限速酶、生理意义）调课通知 6/10 9/10； 7/10 10/10 9/10 周六 1-2节 N1-B2054.4 Pentose Phosphate Pathway Definition：G pentose-P + NADPH+H+ pentose-P F-6-P + Gly-3-P 1. Procedure Two phas

19、es Oxidative reactions pentose-P，NADPH+H+，CO2 Nonoxidative reactions a series of group transferThe First PhaseThe Second Phase C5C5C5C3C3C6C6C7C42C2C3Cw 3C5 2C6+ C3基团转移反应2. Features of Pentose Phosphate Pathway Location：cytosol Group transfer Products：ribose-5-P & NADPH Key enzyme Glucose-6-phos

20、phate dehydrogenase inhibitorNADPH 3. 磷酸戊糖途径的生理意义 为核酸的生物合成提供核糖 提供NADPH+H+作为供氢体参与多种代谢反应 是体内许多合成代谢的供氢体 参与体内羟化反应 维持谷胱甘肽(GSH)的还原状态 例：蚕豆病 还原型氧化型4.5 Glycogenesis and Glycogenolysis 糖原(glycogen) 是动物体内糖的储存形式, 是机体能迅速动用的能量储备 种类 肝糖原：70100g 血糖的重要来源 肌糖原：180300g 肌肉收缩的应急能源 Structure of Glycogen -1,4-糖苷键 -1,6-糖苷键 非

21、还原端 1. Glycogenesis Glycogenesis： GGlycogen Location Tissues：liver & muscle Cell：cytosol Procedure GG-6-P G-6-PG-1-P synthesis of UDPG synthesis of glycogenG-6-PG-1-POCH2OPO3H2OHOHOHOHHHHHOCH2OHOHOHOHHHHHOPO3H2磷酸葡萄糖变位酶UDPG (uridine diphophate glucose) Active form of G (G donor） Other active form

22、s：acetyl-CoA， ATPSynthesis of Glycogenw Glycogenn + UDPG Glycogenn+1+ UDPw Glycogen primerw Branching enzyme glycogen synthaseUDPATPUTPADPFeatures of Glycogenesis Donor of glucose：UDPG Key enzyme：glycogen synthase Energy-requiring：2ATP Glycogen primer2. Glycogenolysis Definition：Liver glycogenG Loca

23、tion：cytosol Procedure : from non-reducing end Glycogen G-1-P G-6-P Liver： Muscle：glycolysis/aerobic oxidation Key enzyme：phosphorylase Debranching enzyme Products: G-1-P(85%) + G(15%）phosphorylase glucose-6-phosphataseGGlycogen Phosphorylase3. Regulation of Glycogenesis & Glycogenolysis Key enz

24、ymes Glycogen synthase(GS) Glycogen phosphorylase(GP) Pattern of regulation covalent modification allosteric regulationCovalent Modification GS GS-P (+) (-) GP GP-P (-) (+) Cascade system Amplification Every level can be regulated共价修饰调节特点 两种酶磷酸化或去磷酸化后活性变化相反 快速调节 具有级联放大效应，效率高 受激素调节 胰高糖原分解，糖原合成 Allost

25、eric Regulation GS activators- ATP, G-6-P GP activator-AMP inhibitors-ATP, G-6-P Ca2+思考题 1分子糖原通过糖酵解净生成( )分子ATP?Glycogen is very limited 210mg G/kg/h 210 X 50kg X 10h=105g G4.6 Gluconeogenesis Definition non-carbohydratesglucose/glycogen Substrates lactate glycerol glucogenic amino acids Location Tis

26、sues： liver , kidney Cell：cytosolmitochondria 1. Gluconeogenic Pathway PyruvateGlucose PyruvatePEP 胞液、线粒体线粒体 Energy-requiring：2ATP How oxaloacetate goes into mito from cytosol? oxaloacetatemalate oxaloacetateAsp Source of NADH+H+ lactate：LDH glucogenic AA ：NADH+H+ in mito TCA/-oxidation F-1,6-2P F-6

27、-P6-1 果糖双磷酸酶-1 G-6-P G葡萄糖-6-磷酸酶其它原料的糖异生途径 甘油：3-磷酸甘油磷酸二羟丙酮 乳酸：丙酮酸草酰乙酸天冬氨酸 Ala等生糖AA: 丙酮酸草酰乙酸苹果酸 生糖AA：TCA中间产物草酰乙酸苹果酸 二、糖异生的调节 两个底物循环(substrate cycle) F-6-PF-1,6-2P PEP 丙酮酸 无效循环(futile cycle)糖酵解糖异生糖酵解糖异生糖异生调节举例饥饿：胰高PKAPFK-2 F-2,6-2P糖异生饥饿：胰高F-2,6-2PF-1,6-2P 糖酵解 3. 糖异生的生理意义 维持血糖水平恒定脑、红细胞、骨髓、神经等 G饥饿：脂肪分解甘油

28、G 蛋白质分解生糖AAG 补充肝糖原: 三碳途径 G三碳化合物(丙酮酸、乳酸) 糖原 调节酸碱平衡G4. Lactate Cycle (Cori Cycle） 乳酸循环的形成是由于肝和肌肉中酶的特点不同 耗能: 6ATP 生理意义 避免乳酸的损失 防止因乳酸堆积引起酸中毒 思考题 比较糖异生和糖酵解的异同 （部位、途径、限速酶、能量、生理意义） 谷氨酸是如何异生成糖的？4.7 血糖及其调节 血糖：血中的葡萄糖 血糖水平：血中葡萄糖浓度 正常血糖浓度：3.896.11mmol/L 血糖的来源和去路 1. 血糖的来源和去路血糖食物糖肝糖原非糖物质氧化分解糖原合成磷酸戊糖途径等脂类、氨基酸代谢消化吸收分解糖异生CO2 + H2O肝、肌糖原其它糖脂肪、氨基酸等血糖恒定的生理意义 保证重要器官的能量供应 脑组织正常情况下主要依赖葡萄糖供能 红细胞完全依赖葡萄糖获能 骨髓及神经组织经常利用葡萄糖供能 2. 血糖水平的调节 血糖水平恒定是糖、脂肪、氨基酸代谢协调的结果，也是肝、肌肉、脂肪组织等各器官组织代谢协调的结果 进食： G 糖的氧