生物化学：Chapter4 Metabolism of Carbohydrates

1、Chapter 6 Metabolism of carbohydratesChapter7 Metabolism of LipidsChapter8 Biological oxidation,Metabolism metabolic pathways(代谢途径) metabolic intermediates(代谢中间(产)物)称为metabolites (代谢物,enzyme-catalyzed reactions,Catabolism (degradation) 分解代谢 S P1 + P2 energy Anabolism (biosynthesis) 合成代谢 S1+S2 P ener

2、gy *S: substrate,E1 E2 E3 E4 E5,E1 E2 E3 E4 E5,There are two major types of Metabolic Pathways,Energy relationships between catabolic and anabolic pathways Catabolic pathways deliver chemical energy in the form of ATP, NADH, NADPH, and FADH2. These energy carriers are used in anabolic pathways to co

3、nvert small precursor molecules into cell macromolecules,ATP (adenosine triphosphate) is a nucleotide(核苷酸) composed of three basic units: phosphate, ribose(核糖), adenine(腺嘌呤) (guanine for GTP, uracil for UTP, cytosine for CTP,腺苷三磷酸,AMP,ATPADP + Pi energy ATPAMP + PPi energy Pi Pi,ATP provides energy

4、by hydrolysis or group transfer (donating a Pi, PPi or AMP to form covalent intermediates,Although metabolism embraces hundreds of different enzyme-catalyzed reactions, our major concern is the central metabolic pathways, which are few in number and remarkably similar in all forms of life,Chapter 6

5、Metabolism of carbohydrates,Carbohydrates can be synthesized from CO2 in photosynthetic organisms In plants, CO2 + H2O glucose Starch (storage) In animals, * Carbohydrates are synthesized from fat and protein. * The bulk of carbohydrates come from plants (food,自养型生物,异养型生物,葡萄糖,果糖,hexoses,Disaccharide

6、s (二糖) e.g. lactose (乳糖): Glc-Gal sucrose (蔗糖): Glc-Fru maltose(麦芽糖): Glc-Glc trehalose (海藻糖): Glc-Glc * Polysaccharides(多糖) starch (Plant glucose storage) glycogen (Animal glucose storage) cellulose (in plant cell walls) & chitin(in animals) are structural polysaccharides (纤维素&壳多糖,Starch the most i

7、mportant food source of carbohydrate (e.g bread, rice, noodles, potatoes), is a polymer of glucose residues joined by 1,4 bonds and with branches provided by 1,6 bonds,Glycogen (mainly in liver and skeleton muscles) is a polymer of (a1-4) linked glucose units with (a1-6) linked branches (occurring a

8、bout once every 10 glucose residues, making glycogen a highly branched molecule,Glycogen,v,glycogen,Food starch is the main source of carbohydrates. Only monosaccharides can be absorbed in intestine,Section I Digestion and absorption of carbohydrates,maltose (麦芽糖) (40%) - maltotriose(麦芽三糖)(25,limit

9、dextrin(-极限糊精)(30%) isomaltose(异麦芽糖)(5,Glucose(葡萄糖,salivary -amylase 唾液中的-淀粉酶,glucosidase (-葡萄糖苷酶,limit dextrinase (极限糊精酶,Digestion,肠粘膜上皮细胞Intestinal mucosal cell,in mouth,肠腔 (in small intestine,pancreatic -amylase 胰液中的-淀粉酶,Starch in food,Transport of glucose into cells,Facilitated transport Mediate

10、d by a family of at least five glucose transporters in the cell membrane, GLU-1 to GLU-5. Extracellular glucose binds to the transporter, which then alters its conformation, discharging glucose within the cell,ADP+Pi,ATP,G,Na,K,小肠粘膜细胞,肠腔,门静脉,吸收机制,Na+依赖型葡萄糖转运体 (Na+-dependent glucose transporter, SGLT

11、,刷状缘,细胞内膜,Intestinal mucosal cell,吸收途径 肠腔glucose + Na+ Na+-dependent glucose transport protein (SGLT) Intestinal mucosal cell 门静脉 glucose transporter (GLUT15) liver blood other tissue cells,Glc,Na+依赖型葡萄糖转运体,Catabolism of Carbohydrates Three major pathways: 1. Glycolysis(糖酵解或糖的无氧氧化) 2. Aerobic oxidat

12、ion(糖的有氧氧化 ) 3. Pentose phosphate pathway,2ATPs are produced,Glycolysis comes from the Greek glykys, meaning “sweet”, and lysis, meaning “splitting,Section II Glycolysis or Anaerobic Oxidation,enzyme-catalyzed reactions,1 glucose 2 pyruvate 2 lactate,In glycolysis, a molecule of glucose is degraded

13、in a series of enzyme-catalyzed reactions to yield two molecules of three-carbon compound pyruvate, with energy conserved as ATP and NADH. It occurs in cytosol of all organisms,葡萄糖 6 C,丙酮酸 3 C,乳酸,缺O2,lactate,NAD,2H,1) Glucose+ATPGlucose-6-phosphate(G-6-P) + ADP phosphorylation of Glc to form G-6-P,H

14、exokinase (also glucokinase葡萄糖激酶 in liver) catalyzes the first phosphorylation reaction. 1 ATP molecule is consumed,Irreversible,己糖激酶,Hexokinase Hexokinase comprise hexokinase, & Hexokinase, catalyze phosphorylation of hexose to form hexose-6-phosphate These enzymes can be inhibited by their product

15、s These enzymes have high affinity for glucose,Hexokinase (or glucokinase) Catalyze phosphorylation of Glc to form G-6-P Only distribute in liver Can not be inhibited by G-6-P Has low affinity for glucose Can be regulated by some hormones (e.g. insulin induce synthesis of E protein) Helps regulate b

16、lood glucose in the liver,2) G-6-P Fructose-6-phosphate (F-6-P,Phosphohexose isomerase catalyzes the isomerization from G-6-P to F-6-P, converting an aldose to a ketose. * This reaction is reversible,磷酸己糖异构酶,3) F-6-P + ATP Fructose-1,6-bisphosphate (F-1,6-BP) + ADP,Phosphofructokinase-1 (PFK-1) cata

17、lyzes the reaction. The reaction is irreversible. In the reaction,one ATP molecule is consumed,6-磷酸果糖激酶-1,3,2,1,4,5,6,F-1,6-BP Dihydroxyacetone phosphate + Glyceraldehyde-3-phosphate,One molecule of hexose is cleaved from the middle C-C bond to yield two molecules of triose. The reaction is reversib

18、le,The “lysis” step,DHAP,磷酸二羟丙酮）,PGAL,3-磷酸甘油醛,醛缩酶,5) Dihydroxyacetone phosphate Glyceraldehyde-3- phosphate,磷酸丙糖异构酶,6) Glyceraldehyde-3-phosphate + NAD+ Pi 1,3-bisphosphoglycerate + NADH,Enzyme: glyceraldehyde-3-phosphate dehydrogenase Coenzyme: NAD,3-磷酸甘油醛脱氢酶,High energy acyl phosphate,NAD and NADP

19、 are the freely diffusible coenzymes of many dehydrogenases, used in redox reactions. Both NAD+ and NADP+ accept two electrons and one proton,nicotinamide ring,7) 1,3-bisphosphoglycerate + ADP 3-phosphoglycerate + ATP,Enzyme: phosphoglycerate kinase Generate one molecule of ATP,磷酸甘油酸激酶,ATP is formed

20、 by the direct transfer of a phosphate group from a high-energy substrate (eg. glycerate-1,3-bisphosphate) to ADP. 代谢物在脱氢或脱水过程中产生的高能磷酸键直接转移给ADP生成ATP的过程,Substrate-level phosphorylation 底物水平磷酸化,8) 3-phosphoglycerate 2-phosphoglycerate,Enzyme: phosphoglycerate mutase Transfer of the phosphoryl group fr

21、om C3 to C2,磷酸甘油酸变位酶,9) 2-phosphoglycerate Phosphoenolpyruvate (PEP) + H2O,烯醇化酶,High energy,Enzyme: pyruvate kinase Produce one ATP molecule by substrate-level phosphorylation The reaction is irreversible,10) PEP +ADP Pyruvate + ATP,丙酮酸激酶,Three possible catabolic fates of the pyruvate formed in glyc

22、olysis,O2,缺O2,缺O2,Under anaerobic conditions, pyruvate is reduced to lactate in a reaction catalyzed by lactate dehydrogenase, NAD+ as coenzyme. This occurs to regenerate NAD+ for the glycolysis pathway to continue when O2 lacks,Pyruvate + NADH +H+ Lactate + NAD,11) Pyruvate is converted to lactate

23、under anaerobic conditions,LDH,lactate,NAD,2H,Pyruvatelactate 丙酮酸生成乳酸,2,All enzymes are in the cytosol. A net gain of two ATP, two lactates are resulted when a glucose molecule is oxidized via the glycolysis pathway: Glucose + 2 ADP + 2Pi 2 lactate + 2ATP + 2H2O Net NADH production is zero Substrate

24、-level phosphorylation phosphoglycerate kinase pyruvate kinase,Summary of Glycolysis,Three irreversible reactions: (1) Glucose + ATP G-6-P + ADP hexokinase (glucokinase) (2) F-6-P + ATP F-1, 6-2P + ADP phosphofructokinase-1 (3) Phosphoenolpyruvate+ADP Pyruvate+ATP pyruvate kinase These three reactio

25、ns are the major regulation points of glycolysis,Summary of Glycolysis,2 ATP,Hexokinase,Phosphofructokinase,Pyruvate kinase,1 ATP,Net production = 2 ATP,1 ATP,Phosphoglycerate kinase,2 ATP,Energy yield,Summary of Glycolysis,Summary of Glycolisis,3 irreversible / key reactions catalyzed by Hexokinase

26、 (glucokinase) 6-phosphofructokinase-1 Pyruvate kinase Key enzyme activities are controlled by Allosteric regulation Chemical modification Enzyme concentration,2. Regulation of glycolysis,lactate,6-phosphofructokinase-1 (PFK-1) is the main regulation point for controlling the rate of glycolysis,Phos

27、phofructokinase-1 (PFK-1) is regulated by * Allosteric regulation,F-2,6-BP is very strong allosteric activiator,Chemical modification PFK-2 and FBP-2 is controlled by glucagon (胰高血糖素) through chemical modification,柠檬酸,Fructose 1,6-bisphosphate,PFK-2/FBP-2 受胰高血糖素的（化学修饰）调节,The most important role of g

28、lycolysis is to supply energy (ATP) rapidly in anaerobic condition. (e.g. skeletal muscles contract vigorously in anaerobic condition). The glycolysis is also important for some tissue cells to get energy in aerobic condition: It is the sole source of energy in erythrocytes (no mitochondria) It prov

29、ides energy in some mammalian tissues and cell types with very high metabolic activity (nerve cells, white blood cell, and marrow cell, for example,3. Physiological roles of glycolysis,Under aerobic conditions, NADH in cytosol are transported into mitochondria by two shuttle systems. NADH will pass

30、their electrons to O2 after being transferred through a series of electron transport chain. The complete oxidation of NADH leads to the generation of ATP,anaerobic conditions,GlucoseCO2 + H2O +ATPs Aerobic oxidation is major pathway 50%70% of energy comes from glucose oxidation in human body Almost

31、all cells get energy from aerobic oxidation of glucose Occurs in cytosol & in mitochondrion,Section Aerobic Oxidation of Glucose,O2,Stage I: Glucose 2 Pyruvate (In cytosol) Stage II: Pyruvate Acetyl-CoA (Pyruvate must be transported into the mitochondrion) Stage III: Acetyl-CoA CO2 +H2O (Citric acid

32、 cycle + ETC in mitochondrion,ETC,1. Three stages of Aerobic Oxidation,乙酰CoA,Hydrogen (NADH, FADH2 by dehydrogenation during catabolism,O2,a series of membrane-bound electron carriers, called the respiratory chain or electron transfer chain,H2O,ADP + Pi ATP,energy,H H+ + e,Oxidation,Phosphorylation,

33、氧化磷酸化 (Oxidative phosphorylation,Mitochondria is the major site for fuel oxidation to generate ATP,1) First Stage: (In cytosol) Glucose 2 ATP 2 NAD+ 2 pyruvate 4 ATP 2 NADH,Glycolytic pathway,Pyruvate is first transported into mitochondria via a specific transporter on the inner membrane. Pyruvate i

34、s converted to acetyl-CoA and CO2 by oxidative decarboxylation in mitochondria,Pyruvate Acetyl-CoA,Pyruvate + NAD+ + HSCoA Acetyl-CoA + NADH+H+ + CO2,Enzyme: pyruvate dehydrogenase complex Oxidative decarboxylation (氧化脱羧): combination of two reactions,丙酮酸脱氢酶复合体,The pyruvate dehydrogenase (PDH) compl

35、ex is a huge multimeric assembly of three kinds of enzymes each present in multiple copies, having over 60 subunits. pyruvate dehydrogenase (E1) 丙酮酸脱氢酶 dihydrolipoyl transacetylase (E2)二氢硫辛酰胺转乙酰酶 dihydrolipoyl dehydrogenase (E3)二氢硫辛酰胺脱氢酶 5 coenzymes: thiamine pyrophosphate (TPP,B1), lipoic acid(硫辛酸)

36、, NAD+ (PP), FAD (B2), HSCoA (泛酸,Coenzyme A (CoA-SH), synthesized from pantothenic acid (Vitamin B5) is the “carrier molecules” deliver activated acyl groups (with 2-24 Carbons) for degradation or biosynthesis. Functional group: sulfhydryl group (-SH,FAD and FMN, the flavin nucleotides, are derived

37、from riboflavin (VitaminB2). They serve as tightly bound prosthetic groups of flavoproteins. The oxidized flavin nucleotide can accept either one electron (yielding FADH1 or FMNH1) or two (yielding FADH2 or FMNH2,Dihydrolipoyl,The lipoyl group occurs in oxidized (disulfide) and reduced (dithiol) for

38、ms and acts as a carrier of both hydrogen and an acetyl (or other acyl) group,All these enzymes and coenzymes are clustered, allowing the intermediates to react quickly without diffusing away from the surface of the enzyme complex, and the local concentration of the substrate is kept very high,The o

39、xidative decarboxylation of pyruvate is catalyzed by a multiezyme complex: pyruvate dehydrogenase complex,Hydroxyethyl TPP,catalytic cycle,3) The third stage Acetyl-CoA TCA Oxidative phosphorylation CO2 + H2O + ATP,2. Tricarboxylic acid cycle, TCA (Citric acid cycle / Krebs cycle,The common pathway

40、leading to complete oxidation of carbohydrates, fatty acids, and amino acids to CO2. A pathway providing many precursors for biosynthesis,The acetyl CoA is completely oxidized to CO2 via the citric acid cycle,1） Oxaloacetate + Acetyl-CoA Citrate + HSCoA,Enzyme: citrate synthase,1) The citric acid cy

41、cle consists of eight reactions,草酰乙酸,乙酰CoA,2) Citrate is converted to isocitrate via dehydration followed by a hydration step,Enzyme: aconitase 顺乌头酸酶,异柠檬酸,顺乌头酸,3) Isocitrate+NAD+-Ketoglutarate+NADH +H+ + CO2,Enzyme: isocitrate dehydrogenase Oxidative decarboxylation step,The first oxidation step,酮戊二

42、酸,4) -Ketoglutarate+NAD+ SuccinylCoA+NADH +H+ + CO2,The second oxidation step,E1, E2, E3,TPP lipoate FAD,Enzyme:-ketoglutarate dehydrogenase complex closely resembles the pyruvate dehydrogenase complex in structure and function The second oxidative decarboxylation step,酮戊二酸脱氢酶复合体,琥珀酰CoA,5）Succinyl-C

43、oA + GDP Succinate + GTP,Substrate-level phosphorylation of GDP (or ADP) to form GTP (or ATP,琥珀酰CoA合成酶,琥珀酸,GTP + ADP = GDP + ATP,6） Succinate + FAD Fumarate + FADH2,Enzyme：succinate dehydrogenase (An enzyme bound to the inner membrane of mitochondrion,The third oxidation step,延胡索酸,7） Fumarate + H2O

44、malate,trans,延胡索酸酶,苹果酸,8） Malate +NAD+ Oxaloacetate+NADH+H,The fourth oxidation step,Oxaloacetate is regenerated at the end,The citric acid cycle,Summary of reactions,4 dehydrogenation : 3 NADH+H+, 1 FADH2 2 decarboxylation: 2CO2 1 substrate-level phosphorylation: GDPGTP ATP 3 irreversible reactions

45、: Citrate synthase Isocitrate dehydrogenase -ketoglutarate dehydrogenase,It is the final oxidation pathway of carbohydrates, lipids and proteins. Carbohydrates, lipids and proteinsacetyl-CoA TCA H2O + CO2 + ATP It is the linkage among the metabolic pathways of carbohydrates, lipids and proteins (An

46、amphibolic pathway serving both the catabolic and anabolic). It provides precursors for the biosynthesis of amino acids, nucleotides, fatty acids, sterols, heme groups, etc. e.g. acetyl-CoA - fatty acid and cholesterol oxaloacetae - aspartate -ketoglutarate - glutamate,2) Physiological roles of Citr

47、ic Acid Cycle,NADH enters the respiratory chain to produce 2.5 molecules of ATP. FADH2 enters the respiratory chain to yield 1.5 molecules of ATP,Yield of ATPs in oxidation of 1 acetyl-CoA 1 acetyl-CoA Citric acid cycle & ETC 3 NADH+H+ 3 2.5 = 7.5 ATP 1 FADH2 1 1.5 = 1.5 ATP 1 GTP 1 ATP 10 ATP,3. Ae

48、robic oxidation of glucose is the major way for human bodies to acquire energy (ATP,H2O,H2O,H2O,H2O,2.5ATP,1.5ATP,2.5ATP,2.5ATP,ETC,ETC,ETC,ETC,TCA cycle,Electron transfer chain (ETC) in mitochondria(线粒体电子传递链/呼吸链,NADH electron transfer chain NADH- H2O ATP ATP ATP FADH2 electron transfer chain FADH2-

49、 H2O ATP ATP,Chapter 8,O2,O2,Yield of ATP Glucose 2 pyruvate (Glycolysis) 2 +2NADH (Glycolysis in cytosol)* 3 or 5 2 Pyruvate 2 acetyl-CoA 22.5=5 2 Acetyl-CoA 4CO2 (Citric acid cycle) 210 30 or 32 ATP,Aerobic Oxidation of Glucose,两种穿梭系统(Shuttle system,细胞质中的NADH通过不同的穿梭系统进入线粒体氧化产生的ATP数目不同。 NADH -磷酸甘油穿

50、梭 FADH 1.5ATP NADH 苹果酸-天冬氨酸穿梭 NADH 2.5ATP,细胞质,线粒体,4. Regulation of aerobic oxidation based on the energy requirement of cell,Pyruvate dehydrogenase complex by allosteric regulation allosteric inhibition: by acetyl-CoA, NADH, ATP, fatty acids allosteric activiation：by CoASH, NAD+,AMP, ADP by chemical

51、 modification： phosphorylation /dephosphorylation * The activity of phosphorylated pyruvate dehydrogenase is decreased,共价修饰调节,Regulation of TCA cycle,Citrate synthase Isocitrate dehydrogenase -ketoglutarate dehydrogenase inhibited by NADH / NAD+, ATP / ADP and ATP/AMP activated by Ca2+ in mitochondr

52、ion The rate of electron transfer chain,Glycolysis and Aerobic Oxidation of glucose,glycolysis Aerobic Oxidation in anaerobic condition in aerobic condition in cytosol in mitochondrion end product lactate end product CO2+H2O 2 ATP 30ATP/32ATP,5. Pastuer effect(巴斯的效应,The glycolysis process can be inh

53、ibited by aerobic oxidation,Section Other metabolic pathways of glucose,This pathway occurs in cytosol This pathway does not generate ATP, but can produce 2 very important substances: NADPH Ribose-5-phosphate,1. Pentose phosphate pathway,This pathway can be divided into 2 phases: Oxidative non-rever

54、sible phase producing NADPH Non-oxidative reversible phase producing ribose and other sugars,1) Reactions of pentose phosphate pathway,a series of rearrangement and group transfer reactions,6-磷酸葡萄糖酸内酯,6-磷酸葡萄糖酸,5-磷酸核酮糖,3,Stage 1,Stage 2: Regeneration of six-carbon Glucose-6-P from five-carbon Ribose-

55、5-P,Nonoxidative reactions: a series of rearrangement and group transfer reactions,6NADPH + 3 CO2 3 R-5-P R-5-P pathway 2 F-6-P 1 PGAL,nucleotide and nucleic acid synthesis,3,reductive reaction,Key enzyme: G-6-P dehydrogenease Regulated by NADPH/NADP,2) Physiological roles of pentose phosphate pathw

56、ay,Provision of ribose 5-phosphate residues for nucleotide and nucleic acid synthesis. Generation of NADPH needed for reductive biosynthesis or to counter the damaging effects of oxygen radicals For reductive reaction-fatty acid, cholesterol, etc For hydroxylation reactionsynthesis of collagen, amin

57、o acid, vitamin D3, steroid hormones, bile acids and biotransformation in liver For maintenance of GSH level,hemolysis溶血 hemolytic anemia 溶血性贫血,谷胱甘肽过氧化物酶,谷胱甘肽还原酶,Favism (蚕豆病,Oxidative damage to lipids, protein, enzymes, intact of RBC membrane, Hb, DNA,defect,Section Metabolism of glycogen ( glycogen

58、esis and glycogenolysis,Glycogen (animals) is the major storage form of carbohydrates. liver glycogen (stored in liver) maintenance the balance of the blood glucose muscle glycogen (stored in muscle) be oxidized to generate ATPs for muscle contraction,1,4 glycosidic linkage,1,6 glycosidic linkage,Gl

59、ycogen,OH,hemiacetal hydroxy group 半缩醛羟基,Each glycogen molecule has only one reducing end, but many nonreducing ends,Glycogen is synthesized by using UDP-glucose: G G-6-P E: hexokinase G-6-P G-1-P E: phosphoglucomutase UTP + G-1-P PPi + UDP-glucose(UDPG) E: UDPG pyrophosphorylase PPi: pyrophosphate

60、2Pi,1. Glycogen synthesis (glycogenesis,Occur in cytosol of liver cells and muscle cells,Active form of glucose,Glucose 1-phosphate,UDP-glucose pyrophosphorylase,ATP,UDPG + (G)n (G)n+1 + UDP (primer or glycogen) glucogen(n+1) E1: glycogen synthase (1218 G) forming-1,4-linkage E2: branching enzyme (t