生物化学课件-第11章糖代谢.ppt

1、 生物化学教材及参考书生物化学教材及参考书l教科书教科书lPrinciples of Biochemistry, H.R. Horton等编著等编著 第四版第四版l教学参考教学参考书书 l 生物化学生物化学 ,王王镜镜岩主岩主编编,第三版第三版 高等教育出版社高等教育出版社l Biochemistry , J.M. Berg 等等编编著著l Biochemistry , C.K. Mathews 等等编编著著l Principles of Biochemistry , A.L. Lehninger等等编编著著l 生物化学生物化学 ,张张曼夫主曼夫主编编 中国中国农业农业大学出版社大学出版社l

2、动动物生物化学物生物化学 ,周周顺顺伍等主伍等主编编 第三版第三版 中国中国农业农业大学出版社大学出版社第十一章糖代谢第十一章糖代谢Key Termslglycolysisllactic acid fermentationlalcoholic fermentationlgluconeogenesislobligate anaerobelfacultative anaerobelhexokinaselkinaselphosphofructokinase (PFK)lthioester intermediatelsubstrate-level phosphorylationlmutaselenol

3、 phosphatelpyruvate kinaselbifunctional enzymelfeedforward stimulationlcommitted steplpyruvate carboxylaselbiotinlglucose 6-phosphataselsubstrate cyclelCori cyclelII. Transducing一一 糖的生理功能糖的生理功能l构成组织和细胞的成分（构成组织和细胞的成分（核糖，粘核糖，粘多糖，细胞膜，神经组织）多糖，细胞膜，神经组织）l氧化供能（氧化供能（1克克葡萄糖葡萄糖完全氧化可放完全氧化可放出出4千卡能量千卡能量）l转变成其他物质

4、转变成其他物质二二 糖的来源与去路糖的来源与去路来源：来源：l消化道吸收；不同动物有不同的形式消化道吸收；不同动物有不同的形式l非糖物质转变而来：肝脏中的糖异生非糖物质转变而来：肝脏中的糖异生去路：小肠吸收去路：小肠吸收肝：合成糖原肝：合成糖原 氧化供能氧化供能 进入血液进入血液 机体组织细胞机体组织细胞 转变成其他物质转变成其他物质机体组织细胞：合成肌糖原机体组织细胞：合成肌糖原 氧化供能氧化供能 转变成其他物质转变成其他物质三三 糖原的合成与分解糖原的合成与分解 糖原的合成糖原的合成糖原的分解糖原的分解Glycogen Structure. In this structure of two

5、 outer branches of a glycogen molecule, the residues at thenonreducing ends are shown in red and residue that starts a branch is shown in green. The rest of the glycogen moleculeis represented by R.Electron Micrograph of a Liver Cell. The dense particles in the cytoplasm are glycogen granules.Courte

6、sy of Dr. George Palade.Fates of Glucose 6-Phosphate. Glucose 6-phosphate derived from glycogen can (1) be used as a fuel foranaerobic or aerobic metabolism as in, for instance, muscle; (2) be converted into free glucose in the liver andsubsequently released into the blood; (3) be processed by the p

7、entose phosphate pathway to generate NADPH or ribosein a variety of tissues.An Overview of Glycogen Metabolism Glycogen degradation and synthesis are relatively simple biochemical processes. Glycogen degradation consists of three steps: (1) the release of glucose 1-phosphate from glycogen, (2) the r

8、emodeling of the glycogen substrate to permit further degradation, and (3) the conversion of glucose 1-phosphate into glucose 6-phosphate for further metabolism. The glucose 6-phosphate derived from the breakdown of glycogen has three fates (Figure 21.3): (1) It is the initial substrate for glycolys

9、is, (2) it can be processed by the pentose phosphate pathway to yield NADPH and ribose derivatives; and (3) it can be converted into free glucose for release into the bloodstream. This conversion takes place mainly in the liver and to a lesser extent in the intestines and kidneys.lGlycogen synthesis

10、 requires an activated form of glucose, uridine diphosphate glucose (UDP-glucose), which is formed by the reaction of UTP and glucose 1-phosphate. UDP-glucose is added to the nonreducing end of glycogen molecules. As is the case for glycogen degradation, the glycogen molecule must be remodeled for c

11、ontinued synthesis. The regulation of these processes is quite complex. Several enzymes taking part in glycogen metabolism allosterically respond to metabolites that signal the energy needs of the cell. These allosteric responses allow the adjustment of enzyme activity to meet the needs of the cell

12、in which the enzymes are expressed. Glycogen metabolism is also regulated by hormonally stimulated cascades that lead to the reversible phosphorylation of enzymes, which alters their kinetic properties. Regulation by hormones allows glygogen metabolism to adjust to the needs of the entire organism.

13、By both these mechanisms, glycogen degradation is integrated with glycogen synthesis. We will first examine the metabolism, followed by enzyme regulation and then the elaborate integration of control mechanisms.（一）糖原合成及参与的酶（一）糖原合成及参与的酶l己糖激酶己糖激酶（Hexokinase）l磷酸葡萄糖变位酶磷酸葡萄糖变位酶lUDP-葡萄糖焦磷酸化酶葡萄糖焦磷酸化酶l糖原合成酶

14、糖原合成酶l分支酶分支酶糖原合成糖原合成 UDP-葡萄糖焦磷酸化酶葡萄糖焦磷酸化酶l6-磷酸葡萄糖磷酸葡萄糖 +UTP UDP-葡萄糖葡萄糖+PPilUDP-葡萄糖焦磷酸化酶葡萄糖焦磷酸化酶: 二磷酸尿苷葡萄糖焦磷酸化酶二磷酸尿苷葡萄糖焦磷酸化酶葡萄糖残基（葡萄糖残基（n）葡萄糖残基（葡萄糖残基（n+1）糖原合成酶糖原合成酶糖原合成酶糖原合成酶分支酶分支酶 糖原合成糖原合成l葡萄糖首先在葡萄糖首先在己糖激酶己糖激酶的作用下转变成的作用下转变成6-磷磷酸葡萄糖，再经几步反应转变成酸葡萄糖，再经几步反应转变成UDP-葡萄葡萄糖，在少量葡萄糖残基（糖，在少量葡萄糖残基（n4）存在下，）存在下，由由n

15、个葡萄糖残基转变成个葡萄糖残基转变成n+1个葡萄糖残基。个葡萄糖残基。当当-1,4糖苷键糖苷键延长延长6个残基以上时，分支酶个残基以上时，分支酶催化一部分残基脱落，以催化一部分残基脱落，以-1,6糖苷键糖苷键与原与原分子中的另一个残基相连，形成分支。然后分子中的另一个残基相连，形成分支。然后再延长，再分支，形成再延长，再分支，形成具有很多分支的糖原。具有很多分支的糖原。 （二）糖原分解及参与的酶（二）糖原分解及参与的酶l磷酸化酶（磷酸化酶（Phosphorylase）关键酶关键酶l变位酶变位酶l6-磷酸葡萄糖酶磷酸葡萄糖酶（只在肝，只在肝， 肾中存在肾中存在）l转移酶转移酶l脱支酶脱支酶转移酶

16、和脱支酶是转移酶和脱支酶是16万万kd的酶的多肽链上的酶的多肽链上的两个活性位点的两个活性位点 磷酸化酶磷酸化酶l糖原糖原(n)+磷酸磷酸1-磷酸葡萄糖磷酸葡萄糖 +糖原糖原(n-1)l1-磷酸葡萄糖磷酸葡萄糖 6-磷酸葡萄糖磷酸葡萄糖 6-磷酸葡萄糖酶（肝，肾）磷酸葡萄糖酶（肝，肾） l6-磷酸葡萄糖磷酸葡萄糖 葡萄糖葡萄糖磷酸化酶磷酸化酶lPhosphoglucomutase Converts Glucose 1-phosphate into Glucose 6-phosphatelLiver Contains Glucose 6-phosphatase, a Hydrolytic Enz

17、yme Absent from Muscle转移酶转移酶脱支酶脱支酶磷酸化酶磷酸化酶转移酶转移酶 糖原分解糖原分解 糖原分解的关键酶是磷酸化酶糖原分解的关键酶是磷酸化酶。该酶与糖原分子非还。该酶与糖原分子非还原性末端结合，形成原性末端结合，形成1-磷酸葡萄糖。然后转变成磷酸葡萄糖。然后转变成6-磷磷酸葡萄糖。酸葡萄糖。6-磷酸葡萄糖在磷酸葡萄糖在6-磷酸葡萄糖酶磷酸葡萄糖酶的作用下的作用下生成生成葡萄糖葡萄糖。此酶只在肝，肾中存在。然后转移酶的。此酶只在肝，肾中存在。然后转移酶的作用使分支减少，分支点作用使分支减少，分支点-1,6糖苷键脱支酶分解。糖苷键脱支酶分解。 转移酶和脱支酶是一个酶的不

18、同部分。转移酶和脱支酶是一个酶的不同部分。 转移酶把三个葡萄糖残基作为一组从外面的分支转移转移酶把三个葡萄糖残基作为一组从外面的分支转移到另一个分支上。到另一个分支上。 脱支酶又称脱支酶又称-1,6葡萄糖苷酶，水解葡萄糖苷酶，水解-1,6糖苷键。糖苷键。Glycogen Remodeling.lFirst, a-1,4-glycosidic bonds on each branch are cleaved by phosphorylase,leaving four residues along each branch. The transferase shifts a block of thr

19、ee glycosyl residues from one outer branchto the other. In this reaction, the a-1,4-glycosidic link between the blue and the green residues is broken and a new a-1,4link between the blue and the yellow residues is formed. The green residue is then removed by a-1,6-glucosidase,leaving a linear chain

20、with all a-1,4 linkages, suitable for further cleavage by phosphorylase.缺乏糖原合成和分解的哪一种酶时会缺乏糖原合成和分解的哪一种酶时会出现如下情况？出现如下情况？ 糖原量大，结构正常，肝增大，严重低血糖，糖原量大，结构正常，肝增大，严重低血糖，酮病等酮病等 糖原量大，外面的分支短，肝增大，糖原量大，外面的分支短，肝增大， 低血低血 糖，酮病等。糖，酮病等。 糖原量正常，分支特长，肝逐渐硬化在糖原量正常，分支特长，肝逐渐硬化在2岁前岁前肝肝 功能丧失致死。功能丧失致死。四四 由遗传病决定的糖原储藏病由遗传病决定的糖原储藏病

21、缺乏缺乏6-磷酸葡萄糖酶的病磷酸葡萄糖酶的病 糖原量大，结构正常，肝增大，严重低血糖，酮糖原量大，结构正常，肝增大，严重低血糖，酮病等病等缺乏脱支酶的病缺乏脱支酶的病 糖原量大，外面的分支短，肝增大，糖原量大，外面的分支短，肝增大， 低血低血 糖，酮病等。糖，酮病等。缺乏分支酶的病缺乏分支酶的病 糖原量正常，分支特长，肝逐渐硬化，在糖原量正常，分支特长，肝逐渐硬化，在2岁前岁前肝肝 功能丧失而致死。功能丧失而致死。SummarylGlycolysis Is an Energy-Conversion Pathway in Many OrganismslGlycolysis is the set

22、of reactions that converts glucose into pyruvate. The 10 reactions of glycolysis take place in thelcytosol. In the first stage, glucose is converted into fructose 1,6-bisphosphate by a phosphorylation, an isomerization,land a second phosphorylation reaction. Two molecules of ATP are consumed per mol

23、ecule of glucose in these reactions,lwhich are the prelude to the net synthesis of ATP. In the second stage, fructose 1,6-bisphosphate is cleaved by aldolaselinto dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, which are readily interconvertible. In the third stage,lATP is generated. Glyc

24、eraldehyde 3-phosphate is oxidized and phosphorylated to form 1,3-bisphosphoglycerate, an acyllphosphate with a high phosphoryl-transfer potential. This molecule transfers a phosphoryl group to ADP to form ATPland 3-phosphoglycerate. A phosphoryl shift and a dehydration form phosphoenolpyruvate, a s

25、econd intermediate with alhigh phosphoryltransfer potential. Another molecule of ATP is generated as phosphoenolpyruvate is converted intolpyruvate. There is a net gain of two molecules of ATP in the formation of two molecules of pyruvate from one moleculelof glucose.lThe electron acceptor in the ox

26、idation of glyceraldehyde 3-phosphate is NAD+, which must be regenerated for glycolysislto continue. In aerobic organisms, the NADH formed in glycolysis transfers its electrons to O2 through the electrontransportlchain, which thereby regenerates NAD+. Under anaerobic conditions and in some microorga

27、nisms, NAD+ islregenerated by the reduction of pyruvate to lactate. In other microorganisms, NAD+ is regenerated by the reduction oflpyruvate to ethanol. These two processes are examples of fermentations.The Glycolytic Pathway Is Tightly ControlledlThe glycolytic pathway has a dual role: it degrades

28、 glucose to generate ATP, and it provides building blocks for thelsynthesis of cellular components. The rate of conversion of glucose into pyruvate is regulated to meet these two majorlcellular needs. Under physiologic conditions, the reactions of glycolysis are readily reversible except for the one

29、slcatalyzed by hexokinase, phosphofructokinase, and pyruvate kinase. Phosphofructokinase, the most important controlelement in glycolysis, is inhibited by high levels of ATP and citrate, and it is activated by AMP and fructose 2,6-lbisphosphate. In the liver, this bisphosphate signals that glucose i

30、s abundant. Hence, phosphofructokinase is active whenleither energy or building blocks are needed. Hexokinase is inhibited by glucose 6-phosphate, which accumulates whenlphosphofructokinase is inactive. ATP and alanine allosterically inhibit pyruvate kinase, the other control site, andlfructose 1,6-

31、bisphosphate activates the enzyme. Consequently, pyruvate kinase is maximally active when the energylcharge is low and glycolytic intermediates accumulate.Glucose Can Be Synthesized from Noncarbohydrate PrecursorslGluconeogenesis is the synthesis of glucose from noncarbohydrate sources, such as lact

32、ate, amino acids, and glycerol.lSeveral of the reactions that convert pyruvate into glucose are common to glycolysis. Gluconeogenesis, however,lrequires four new reactions to bypass the essential irreversibility of three reactions in glycolysis. In two of the newlreactions, pyruvate is carboxylated

33、in mitochondria to oxaloacetate, which in turn is decarboxylated and phosphorylatedlin the cytosol to phosphoenolpyruvate. Two high-energy phosphate bonds are consumed in these reactions, which arelcatalyzed by pyruvate carboxylase and phosphoenolpyruvate carboxykinase. Pyruvate carboxylase contains

34、 a biotinlprosthetic group. The other distinctive reactions of gluconeogenesis are the hydrolyses of fructose 1,6-bisphosphate andlglucose 6-phosphate, which are catalyzed by specific phosphatases. The major raw materials for gluconeogenesis by thelliver are lactate and alanine produced from pyruvat

35、e by active skeletal muscle. The formation of lactate during intenselmuscular activity buys time and shifts part of the metabolic burden from muscle to the liver.Gluconeogenesis and Glycolysis Are Reciprocally RegulatedlGluconeogenesis and glycolysis are reciprocally regulated so that one pathway is

36、 relatively inactive while the other islhighly active. Phosphofructokinase and fructose 1,6-bisphosphatase are key control points. Fructose 2,6-bisphosphate, anlintracellular signal molecule present at higher levels when glucose is abundant, activates glycolysis and inhibitslgluconeogenesis by regul

37、ating these enzymes. Pyruvate kinase and pyruvate carboxylase are regulated by other effectorslso that both are not maximally active at the same time. Allosteric regulation and reversible phosphorylation, which arelrapid, are complemented by transcriptional control, which takes place in hours or day

38、s. 糖酵解是在糖酵解是在无氧无氧条件下，条件下，一个分子一个分子葡萄糖葡萄糖降解成二个降解成二个分子分子乳酸乳酸，同时产生同时产生ATPATP的的过程。糖酵过程。糖酵解在解在细胞质细胞质中进中进行，分四大部分行，分四大部分1212步反应。步反应。 五五 糖酵解糖酵解（GlycolysisGlycolysis）糖酵解的概况糖酵解的概况l葡萄糖葡萄糖可被需氧和厌氧的两类有机体可被需氧和厌氧的两类有机体利用，利用，起始阶段的代谢途径是相同的起始阶段的代谢途径是相同的：无氧条件无氧条件下发酵，下发酵，使葡萄糖降解为小分子化合物供使葡萄糖降解为小分子化合物供应机体能量，小分子化合物成了代谢废物，应机体

39、能量，小分子化合物成了代谢废物，到到生物由厌氧进化到需氧有机体生物由厌氧进化到需氧有机体后才将小后才将小分子化合物分子化合物彻底氧化成彻底氧化成COCO2 2和和H H2 2OO，获得，获得更多的能量更多的能量。需氧生物是厌氧生物之后出需氧生物是厌氧生物之后出现的。现的。l无氧的葡萄糖降解过程称为糖酵解，严格无氧的葡萄糖降解过程称为糖酵解，严格的说是的说是1 1摩尔葡萄糖产生摩尔葡萄糖产生2 2摩尔乳酸，无氧摩尔乳酸，无氧酵解共酵解共1212部反应，分四大阶段部反应，分四大阶段。l 1 1，6 6二磷酸果糖生成：二磷酸果糖生成：l 磷酸丙糖生成过程：磷酸丙糖生成过程：l 丙酮酸生成过程：丙酮酸

40、生成过程： 有一步有一步脱氢反应是糖酵解途径中唯一的脱氢反应是糖酵解途径中唯一的，主要是，主要是释放能量使释放能量使ADP ADP ATP. ATP. 有两步底物磷酸化反应有两步底物磷酸化反应。l 乳酸的生成：这是乳酸的生成：这是NADHNADH转变为转变为NAD+(NAD+(为为3-3-磷磷酸甘油醛脱氢反应提供酸甘油醛脱氢反应提供) )的过程的过程l无氧条件下无氧条件下NADH NADH NAD+ NAD+是靠丙酮酸还原为是靠丙酮酸还原为乳酸来完成的乳酸来完成的Figure 18.37. Glycerol 3-Phosphate Shuttle. Electrons from NADH ca

41、n enter the mitochondrial electron transportchain by being used to reduce dihydroxyacetone phosphate to glycerol 3-phosphate. Glycerol 3-phosphate is reoxidizedby electron transfer to an FAD prosthetic group in a membrane-bound glycerol 3-phosphate dehydrogenase. Subsequentelectron transfer to Q to

42、form QH2 allows these electrons to enter the electron-transport chain. 乳酸发酵乳酸发酵 总反应式总反应式： Glc + 2Pi + 2ADP + 2NAD+ 2 丙酮酸丙酮酸+2ATP+2(NADH + H+) + 2H2O 葡萄糖磷酸化葡萄糖磷酸化 -2 ATP -2底物磷酸化底物磷酸化 2 2 ATP 4糖酵解过程中糖酵解过程中ATP的形成的形成净生成净生成 2ATP 糖酵解的生理意义糖酵解的生理意义l在在无氧或缺氧条件下无氧或缺氧条件下（剧烈运动，重役及（剧烈运动，重役及病理性休克等）为机体病理性休克等）为机体提供生

43、命活动所需提供生命活动所需的能量的能量，但是能量有限。，但是能量有限。l成熟的红细胞仅靠糖酵解来获得能量成熟的红细胞仅靠糖酵解来获得能量l葡萄糖葡萄糖丙酮酸丙酮酸(与糖酵解过程基与糖酵解过程基本相同，但是由于在本相同，但是由于在有氧有氧条件下进条件下进行，行，NADH的去向不同，的去向不同，胞质中进胞质中进行行）l丙酮酸丙酮酸乙乙酰辅酶酰辅酶A（线粒体）（线粒体）l三三羧羧酸循酸循环环（线粒体）（线粒体）六六 葡萄糖有氧氧化葡萄糖有氧氧化（一）葡萄糖（一）葡萄糖丙酮酸丙酮酸葡萄糖葡萄糖丙酮酸丙酮酸 ATPATP的形成的形成 总反应式：总反应式： GlcGlc + 2Pi + 2ADP + 2N

44、AD + 2Pi + 2ADP + 2NAD+ + 2 2丙酮酸丙酮酸+2ATP+2(NADH + H+2ATP+2(NADH + H+ +) + ) + 2H2H2 2OO 葡萄糖磷酸化葡萄糖磷酸化 -2 ATP -2底物磷酸化底物磷酸化 2 2 ATP 42NADH 2 3 ATP 6/42FADH2 2 2 ATP - 净生成净生成 8/6 ATP （二）丙酮酸二）丙酮酸乙酰辅酶乙酰辅酶A A 丙酮酸脱氢酶系丙酮酸脱氢酶系（含三种酶含三种酶,六种辅助因子六种辅助因子）丙酮酸脱氢酶系丙酮酸脱氢酶系三种酶三种酶 丙酮酸脱羧酶丙酮酸脱羧酶 硫辛酸乙酰转移酶硫辛酸乙酰转移酶 二氢硫辛酸脱氢酶二氢

45、硫辛酸脱氢酶六种辅助因子六种辅助因子 NAD+ ，FAD+，辅酶，辅酶A，硫辛酸，硫辛酸， 硫氨素焦磷酸（硫氨素焦磷酸（TPP），镁离子），镁离子 Beriberi-(脚气病）脚气病）lA vitamin-deficiency disease first described in 1630 by JacobBonitus, a Dutch physician working in Java: A certain very troublesome affliction, which attacks men, is calledby the inhabitants Beriberi (which

46、means sheep). I believe those,whom this same disease attacks, with their knees shaking and the legs raised up, walk like sheep. It is a kind of paralysis, or ratherTremor: for it penetrates the motion and sensation of the hands andfeet indeed sometimes of the whole body.The Disruption of Pyruvate Me

47、tabolism Is the Cause of Beriberi and Poisoningby Mercury and ArseniclBeriberi, a neurologic and cardiovascular disorder, is caused by a dietary deficiency of thiamine (also called vitamin B)1 ). The disease has been and continues to be a serious health problem in the Far East because rice, themajor

48、 food, has a rather low content of thiamine. This deficiency is partly ameliorated if the whole rice grain is soaked inwater before milling some of the thiamine in the husk then leaches into the rice kernel. The problem is exacerbated ifthe rice is polished, because only the outer layer contains sig

49、nificant amounts of thiamine. Beriberi is also occasionallyseen in alcoholics who are severely malnourished and thus thiamine deficient. The disease is characterized by neurologicand cardiac symptoms. Damage to the peripheral nervous system is expressed as pain in the limbs, weakness of the musculat

50、ure, and distorted skin sensation. The heart may be enlarged and the cardiac output inadequate.lWhich biochemical processes might be affected by a deficiency of thiamine? Thiamine pyrophosphate is the prostheticgroup of three important enzymes: pyruvate dehydrogenase, a-ketoglutarate dehydrogenase,