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Part Two METABOLISM Wu Yaosheng Metabolism of Carbohydrate Biological Oxidation Metabolism of Lipids Metabolism of Proteins Metabolism of Nucleotides Regulation of Metabolism 制作:吴耀生 目录 Chapter Four Metabolism of Carbohydrates 制作:吴耀生 目录 Main contents 1. Introduction 2. Glycolysis 3. Aerobic oxidation of glucose 4. Pentose phosphate pathway 5. Glycogenesis and glycogenolysis 6. Gluconeogenesis 7. Blood sugar and regulation Disease cases Concepts 制作:吴耀生 Questions 目录 Section One Introduction The physiological functions of saccharides 1. To be oxidized and to supply energy This is the major function of saccharide 2. Work as remarkably versatile precursors for biosynthetic reactions such as amino acid, fat, cholesterol, nucleoside 3. Participate in the composition of tissue cells in organism. Such as glycoprotein, proteoglycan, glycolipid 1. Digestion and Absorption of Carbohydrates 1.1 Digestion of Carbohydrates In nature, starch from plants are the major dietary carbohydrate source for human. Other carbohydrate sources include glycogen, maltose, sucrose, lactose and glucose. Digesting place: Mainly in small intestine, less in mouth. Process of digesting Starch Mouth Stomach Small intestine α-amylase in saliva α-amylase in pancreatic juice maltose+maltotriose (40%) (25%) The surface of the small intestinal epithelial cells α-limit dextrins+isomaltose (30%) (5%) α-limit dextrinase α-glucosidase Glucose The cellulose existing abundant in diet are useful for the human health due to that they can stimulate the moving of intestine, even though they can not be digested because of lacking of -glucosidase in human intestine. 1.2 Absorption of Carbohydrates (1) Absorption place Upside part of small intestine (2) Molecule absorbed Monosaccharide, mainly glucose (3) Mechanism of absorption lumen membrane Intracellular membrane Small intestinal epithelial cell Portal vein K+ Intestine lumen ATP ADP+Pi Na+pump Na+ G Na+-dependent glucose transporter, SGLT 1.4 Absorption route of Carbohydrates Small intestine lumen SGLT Small intestinal epithelial cells SGLT---- Na+ (Sodium)glucose transporter Portal vein GLUT, refer to glucose transporter. There are five kinds of GLUT having been found Various tissue cells Liver GLUT Blood circulation 2. The Fate of Absorbed Glucose glycogen Other substances Transform glycogenesis Pentose ribose phosphate pathway + NADPH+H+ ATP glycogenolysis Glucose glycolysis Aerobic Pyruvate Anaerobic Digestion and absorption Starch H2O and CO2 Gluconeogenesis Lactate, amino acid, glycerol Lactate Section Two Anaerobic degradation of Glucose Glycolysis 1. Basic Process of Glycolysis * Definition of Glycolysis The process in which a molecule of glucose is degraded in a series of enzymatic reactions to yield two molecules of pyruvate or lactate under anaerobic condition is term glycolysis. * The site of glycolysis is cytoplasm. The basic process of glycolysis can be divided into two stages: The first stage The reaction process from glucose to pyruvate is called glycolytic pathway The secondary stage The reaction process from pyruvate to lactate 制作:吴耀生 目录 Glu ATP 1.1 Pyruvate Formation from Glucose ADP G-6-P (1) Glucose is phosphorylated to be glucose-6-phosphate F-6-P ATP ADP F-1,6-2P 3-PGA DHAP NAD+ NADH+H+ hexokinase 1,3-DPGA ADP ATP 3-PGA 2-PGA ADP PEP ATP Pyruvate Glucose-6phosphate Glucose One of key enzymes Now it has been found that there are four kinds of isoenyzme of hexokinase in mammal animals called hexokinase I to IV type, respectively. In liver, it is hexokinase IV, namely glucokinase. The characters of glucokinase are: ① The affinity to glucose is very low (high Km, Km ~10 mmol/L, p131 error) ② It is regulated by hormones Glu ATP ⑵ Glucose-6-phosphate →Fructose6-phosphate ADP G-6-P F-6-P ATP ADP F-1,6-2P 3-GAP DHAP Phosphohexose isomerase NAD+ NADH+H+ 1,3-DPGA ADP ATP 3-PGA 2-PGA PEP ADP ATP Pyruvate Glucose-6-phosphate Fructose-6-phosphate Glu ATP (3) fructose-6-phosphate → Fructose-1,6-bisphosphate ADP G-6-P F-6-P ATP ADP F-1,6-2P 3-GAP DHAP Phosphofructokinase-1 NAD+ NADH+H+ 1,3-DPGA ADP Fructose-6-phosphate ATP Fructose-1,6-bisphosphate 3-PGA 2-PGA PEP ADP ATP Pyruvate One of key enzymes Glu ATP (4) phosphohexose →2 molecules of phosphotriose ADP G-6-P F-6-P ATP ADP F-1,6-2P aldolase 3-GAP DHAP NAD+ NADH+H+ 1,3-DPGA ADP ATP 3-PGA 2-PGA PEP ADP ATP Pyruvate Fructose-1,6bisphosphate Dihydroxyacetone phosphate, DHAP Glyceraldehyde-3phosphate, 3-PGA Glu ATP (5) Phosphotrioses interconverse ADP G-6-P F-6-P ATP phosphotriose isomerase ADP F-1,6-2P 3-GAP DHAP NAD+ NADH+H+ 1,3-DPGA ADP ATP 3-PGA 2-PGA PEP ADP ATP Pyruvate Dihydroxyacetone phosphate Glyceraldehyde-3phosphate Glu ATP (6) glyceraldehyde-3-phosphate→1,3bisphosphoglycerate ADP G-6-P F-6-P ATP ADP F-1,6-2P Glyceraldehyde -3-phosphaste dehydrogenase 3-GAP DHAP NAD+ NADH+H+ 1,3-DPGA ADP ATP 3-PGA 2-PGA PEP ADP ATP Pyruvate Glyceraldehyde -3-phosphaste 1,3-bisphosphoglycerate Glu (7) 1,3-bisphosphoglycerate→3phosphoglycerate ATP ADP G-6-P F-6-P ATP ADP F-1,6-2P Phosphoglyc erate kinase 3-GAP DHAP ADP NAD+ 1,3-bisphosphoglycerate NADH+H+ ATP 3-phosphoglycerate 1,3-DPGA ADP ATP 3-PGA 2-PGA PEP ADP ATP Pyruvate substrate level phosphorylation Glu ATP (8) 3-phosphoglycerate→2phosphoglycerate ADP G-6-P F-6-P ATP ADP F-1,6-2P 3-GAP DHAP Phosphoglycerate mutase NAD+ NADH+H+ 1,3-DPGA ADP ATP 3-PGA 2-PGA PEP ADP ATP Pyruvate 3-phosphoglycerate 2-phosphoglycerate Glu ATP (9) 2-phosphoglycerate →phophoenolpyruvate, PEP ADP G-6-P F-6-P ATP ADP F-1,6-2P 3-GAP DHAP enolase NAD+ NADH+H+ 1,3-DPGA ADP ATP 3-PGA 2-PGA PEP ADP ATP Pyruvate 2-phosphoglycerate phophoenolpyruvate Glu (10) Phosphoenolpyruvate → pyruvate, and yield ATP through substrate level phosphorylation ATP ADP G-6-P F-6-P ATP ADP F-1,6-2P Pyruvate kinase 3-GAP DHAP NAD+ NADH+H+ ADP 1,3-DPGA ADP Phosphoenolpyruvate pyruvate ATP ATP 3-PGA 2-PGA PEP ADP ATP Pyruvate One of key enzymes 1.2 Conversion of Pyruvate to Lactate COOH NADH + H+ NAD+ CHOH C=O CH3 COOH Lactate dehydrogenase, LDH pyruvate CH3 lactate Here, the NADH+H+ in the reaction comes from the six step in the above, the dehydrogenation reaction of 3-phosphoglyceraldehyde E1 Glu G-6-P F-6-P ATP ADP E2 ATP F-1, 6-2P ADP DHAP E1:hexokinase 3-GAP NAD+ NADH+H+ E2: 6-PFK-1 1,3-DPG E3: Pyruvate kinase ADP ATP Glycolysis metabolism 3-PGA lactate NAD+ 2-PGA NADH+H+ ATP ADP Pyruvate E3 PEP glucose Dihydroxyacetone phosphate G-6-P The pathway of glycolysis Glyceraldehyde3-phosphate 1,3-Bisphospho glycerate 3-Phosphoglycerate F-6-P 2-Phosphoglycerate F-1,6-bisphosphate Phosphoenolpyruvate pyruvate lactate 制作:吴耀生 目录 Summary for glycolysis (1) Reaction site:in cytoplasm (2) It is a process to produce energy but without the need for oxygen (3) There are three irreversible reaction steps ATP ADP G hexokinase ATP ADP F-6-P PEP F-1,6-2P PFK-1 ADP G-6-P ATP Pyruvate kinase pyruvate (4) The manner to yield energy and the number of ATP produced. Manner:substrate level phosphorylation The net number of yielding ATP : If to begin from Glucose, 2×2-2= 2ATP If to begin from Glycogen, 2×2-1= 3ATP (5) The fate of the final product lactate To be released into blood stream, and then to be taken into liver metabolized. To be decomposed and utilized further To go into Lactate cycle ( gluconeogenesis) Except for glucose, other hexose can converse to phosphohexose and galactose then go into glycolysis pathway. Galactose kinase Mannose hexokinase Mannose-6phosphate Galactose-1-phosphate Glu ATP ADP G-6-P F-6-P ATP fructose ADP F-1,6-2P pyruvate mutase Glucose-1phosphate Entry of other carbohydrates into glycolysis lactose fructose galactose-1-phosphate uridylyl transferase 制作:吴耀生 目录 2. Regulation of Glycolysis ① hexokinase Key enzymes ② 6-phosphofructokinase-1 ③ pyruvate kinase ① allosteric regulation Regulation models ② covalent modification 2.1 6-phosphofructokinase-1 (PFK-1) * Allosteric regulation Allosteric activators:AMP; ADP; F-1,6-2P; F-2,6-2P Allosteric inhibitors: citric acid; ATP(high conc. ) • F-1,6-2P can positively feedback regulate PFK-1 • There are two binding sites in PFK-1 for ATP: ① substrate-binding site in active center (low conc.) ② allosteric site outside active center (high conc. ) AMP Glucagon Citric acid – + PFK-2 FBP-2 (active) ATP cAMP (inactive) 6-PFK-2 ATP F-6-P activating Phosphoprotein phosphatase PKA F-2,6-2P FBP-2 ATP + ADP lactate P PFK-2 FBP-2 (inactive) (active) ADP –/+ PFK-1 + + F-1,6-2P AMP Pi P Pi + – Citric acid 目录 2.2 Pyruvate kinase (1) Allosteric regulation Allosteric activator: fructose 1,6-bisphosphate Allosteric inhibitors: ATP, Alanine (2) Covalent modification Pi Pyruvate kinase Phosphoprotein phosphatase Pyruvate kinase (active) (inactive) ADP ATP Glucagon PKA, CaM kinase PKA:protein kinase A CaM:Calmodulin P 2.3 Hexokinase Glucose-6-phosphate is an allosteric inhibitor of hexokinase, except for hexokinase IV, glucokinase. Long chain acyl CoA is an allosteric inhibitor of glucokinase 3. The significance of Glycolysis (1) Glycolysis is the emergency energyyielding pathway. (2) Glycolysis is the main way to produce ATP in some tissues, even though the oxygen supply is sufficient In cells without mitochondria, red blood cells In metabolism active cells, retina, testis, skin, medulla of kidney. Section Three Aerobic Oxidation of Glucose Concept The process of complete oxidation of glucose to CO2 and water with release of energy as the form of ATP is termed aerobic oxidation. The place for aerobic oxidation: cytoplasm, and mitochondria 1. Basic Process of Aerobic Oxidation of Glucose G(Gn) Cytoplasm First stage:Glycolytic pathway Secondary stage:The oxidation and decarboxylation of pyruvate Third stage:Tricarboxylic cycle and Oxidative phosphorylation H2O Acetyl CoA mitoch ondria TAC [O] ATP Pyruvate ADP NADH+H+ FADH2 CO2 1.1 Oxidation of Glucose to Pyruvate It is the same as the glycolytic pathway in cytosol discussed above. 制作:吴耀生 目录 1.2 Oxidation of Pyruvate to lactate After pyruvate is transported into mitochondria, it will be oxidized and decarboxylated to be acetyl Co A. The total reaction: NAD+ , HSCoA CO2 , NADH + H+ Pyruvate Pyruvate dehydrogenase complex Acetyl CoA The fates of pyruvate in organism Lactate Alanine Pyruvate Acetyl CoA Oxaloacetate 制作:吴耀生 目录 The composition of pyruvate dehydrogenase complex HSCoA NAD+ enzymes E1:pyruvate dehydrogenase E2:dihydrolipoyl transacetylase E3:dihydrolipoyl dehydrogenase coenzyme TPP lipoic acid(L HSCoA FAD, NAD+ S ) S 1. Formation of hydroxyethyl-TPP CO2 2. Yield of acetyl lipoamide NADH+H+ 5. Yield of NADH+H+ NAD+ CoASH 3. Yield of acetyl CoA 4. Formation of lipoamide 目录 1.3 Tricarboxylic Acid Cycle, TAC Introduction Tricarboxylic Acid Cycle, TAC is called citric acid cycle too, because that the first molecule for the beginning of the cycle is citric acid with three carboxyl groups. It was Krebs who first formally put forward TAC theory, therefore the cycle was called Krebs cycle. Reaction location All reactions related to TAC take place in mitochondria H2O H2O ② ① NADH+H+ H2O CoASH ② NAD+ ①citrate synthase ②aconitase ③isocitrate dehydrogenase ④α-ketoglutarate dehydrogenase complex + NAD GTP GDP ⑤succinyl CoA synthetase Nucleoside diphosphate ⑥succinate kinase dehydrogenase NADH+H+ ⑦ ⑦fumarase ③ ⑧ H2O ADP FADH2 ⑥ ATP FAD ⑧malate dehydrogenase GDP+Pi GTP NAD+ NADH+H+ ④ CO2 ⑤ CO2 CoASH CoASH 目录 Summary for TAC ① Concept of TAC:It means the process in which a molecule of acetyl-CoA combines with the four-carbon dicarboxylic acid oxaloacetate, resulting in the formation of a six-carbon tricarboxylic acid, citrate, following a series of reactions in the course of which two molecules of CO2 are released and oxaloacetate is regenerated. ② The location of TAC is mitochondria ③ The key points of TAC For each cycle of TAC, – One molecule of acetyl CoA is consumed – Undergo through four times of dehydrogenation, two times of decarboxylation, one time of substrate level phosphorylation – Yield one molecule of FADH2, three molecules of NADH+H+, two molecules of CO2, one molecule of GTP. – Key enyzmes: citrate synthase α-ketoglutarate dehydrogenase complex isocitrate dehydrogenase ④ TAC is irreversible cycle ⑤ Intermediates in TAC and other metabolism TAC is the common final steps in the breakdown of foodstuffs, such as carbohydrates, lipids, and proteins. TAC serves as the crossroad for the interconversion among carbohydrates, lipids, and non-essential amino acids, and as a source of biosynthetic intermediates. Oxaloacetate in TAC must be complemented and renovated constantly The source for oxaloacetate: Acetyl CoA CO2 Pyruvate Pyruvate carboxylase oxaloacetate citritic acid Citric acid lyase Malate dehydro genase NADH+H+ malate NAD+ glutamate α-ketogutarate Aspartate transaminase Aspartate 2. ATP Generated in the Aerobic Oxidation of Glucose When H+ + e are transported through respiratory chain, they are completely oxidized to H2O and to yield ATP by coupled ADP phosphorylation. NADH+H+ FADH2 [O] [O] H2O、3ATP H2O、2ATP ATP yielded in the Aerobic Oxidation of Glucose Reaction Coenzyme First stage Glucose→ G-6-P ATP -1 -1 F-6-P → F-1,6-DP 2× 3-GAP → 2× 1,3-DPGA NAD+ 2× 3 or 2 × 2* 2×1 2×1 2× 1,3-DPGA → 2×3-PGA 2 × PEP → 2 × Pyruvate Secondary 2× Pyruvate → 2× Acetyl CoA stage Third stage NAD+ 2×3 2×Isocitric acid → 2×α-ketoglutarate NAD+ 2 ×3 2×α-ketoglutarate → 2×Succinate CoA NAD+ 2×3 2×Succinate CoA → 2×Succinate 2×Succinate → 2×fumarate 2×malate → 2×oxaloacetate 2×1 FAD 2×2 NAD+ 2×3 Net yield 38 (or 36) ATP The result was calculated following old theory, now it is updated 3. The Regulation of Aerobic Oxidation of Glucose Key enzymes ① Glycolysis pathway: Hexokinase Pyruvate kinase 6-phosphofructokinase-1 ② Decarboxylation of pyruvate: Pyruvate dehydrogenase complex ③ TAC:Citric acid synthase α-ketoglutarate dehydrogenase complex Isocitric acid dehydrogenase 3.1 The Regulation of Pyruvate Dehydrogenase Complex (1) Allosteric regulation Allosteric inhibitor:acetyl CoA; NADH; ATP Allosteric activator:AMP; ADP; NAD+; Ca2+ As [acetyl CoA]/[HSCoA] or [NADH]/[NAD+], its activity will be inhibited. (2) Covalent modification regulation ⑵ 共价修饰调节 Acetyl CoA Pyruvate Protein kinase Active pyruvate dehydrogenase complex phosphatase inactive pyruvate dehydrogenase complex Acetyl CoA Insulin 目录 3.2 The Regulation of TAC Acetyl CoA – ATP + ADP ① The effect of ATP、ADP Citric acid synthase Oxaloacetate Citric acid NADH Succinyl CoA Citric acid ② Inhibited by products Isocitrate malate ③ allosteric inhibited by intermediates NADH Isocitrate dehydrogenase FADH2 – ATP + ADP Ca2+ α-ketoglutarate α-ketoglutarate dehydrogenase complex ④ Others, for example, Ca2+ can activate various enzymes. + Ca2+ Succinal CoA – Succinyl CoA NADH GTP ATP Section Four Pentose Phosphate Pathway * Concept of pentose phosphate pathway Pentose phosphate pathway is a process in which ribose-5-phosphate and NADPH+H+ are yielded accompanying the degradation of glucose, and then ribose-5 phosphate can turn to glyceraldehyde -3- phosphate and fructose-6-phosphate further. nicotinamide adenine dinucleotide phosphate ( NADPH , reduced form) 1. Basic Process of PPP * Location in cell:in cytoplasm * Two stages first stage:The oxidative phase to yield pentose phosphate, NADPH+H+ and CO2 secondary stage: Non-oxidative phase, including the transfer of a series of groups 1.1 The oxidative phase H C OH H C OH HO C H H C OH H C G-6-P dehydrogenase C=O NADP+ O CH2O NADPH+H+ ⑴ H C OH HO C H H C OH H C P CH2O Glucose-6-phosphate H 2O O P 6-phosphogluconolactone H C OH H HO C H H C OH H C OH CH2O P 6-phosphogluconate CH2OH G-6-PD NADP+ CO COO— CO2 NADPH+H+ ⑵ C=O C O H C OH H C OH CH2O P Ribulose-5-phosphate Ribose-5-phosphate NADP+ NADPH+H+ NADP+ NADPH+H+ Ribose-5-phosphate G-6-P CO2 • Glurose-6-phosphate dehydrogenase (G6PD) is the first key enzyme for the pathway. • All hydrogen atoms coming from two times of dehydrogenation are accepted by NADP+ to generate NADPH + H+ • Ribose-5-phosphate is a very important intermediate molecule during the pentose phosphate pathway. 1.2 Non-oxidative phase Groups transfer • Pentose-5-phosphate can interconvert with three, four, five, six, seven-carbon sugars under the catalysis of transketolase and transaldolase. Among them, glyceraldehyde-3phosphate and fructose-6-phosphate can go into glycolysis pathway, therefore, PPP can be called pentose phosphate shunt. Non-oxidative phase Ribulose-5-phosphate(C5) ×3 Xylulose-5-P C5 Ribose-5-P C5 Sedoheptulose-7-P C7 Glycerald ehyde -3P C3 Erythrose-4-P C4 Fructose-6-P C6 Xylulose-5-P C5 Glyceraldehyde-3P C3 Fructose-6-P C6 3NADP+ G6PD 3NADP+3H+ 6-phosphogluconolactone (C6)×3 First phase 6-phosphogluconate (C6)×3 3NADP+ 3NADP+3H+ G6PD CO2 Ribulose-5P(C5) ×3 Xylulose-5P C5 3-GAP C3 Ribose-5P C5 Sedoheptulose-7P C7 Erythrose-4P C4 F-6-P C6 Xylulose-5P C5 3-GAP C3 F-6-P C6 Secondary phase Pentose phosphate pathway G-6-P (C6)×3 The sum of total reactions in pentose phosphate pathway are 3×Glucose-6-Phosphate+ 6 NADP+ 2×F-6-P+3-GAP+6NADPH+H++3CO2 2. The Significance of pentose Phosphate Pathway 2.1 To supply ribose-5-phosphate for nucleotide and nucleic acid biosynthesis 2.2 To produce NADPH for reductive synthesis such as fatty acid and steroid biosynthesis To produce NADPH (1) NADPH is the donor of hydrogen for various anabolic metabolism in organism (2) NADPH can participate in the hydroxylation reaction, involving biosynthesis or biotransformation in organism (3) NADPH can keep the reduction of GSH A 2G-SH NADP+ AH2 G-S-S-G GSH NADPH+H+ reducase Section Five Glycogen Formation and Degradation Glycogen They are the major storage model of saccharide in animal, and are the main energy source which can be quickly utilized. • Organs in which can store glycogen and physiological significance Muscle:muscle glycogen,180 ~ 300g, mainly supply to muscle contraction Liver:hepatic glycogen,70 ~ 100g,to keep blood sugar level constant • Structure of glycogen 1. 93% of glucose units are joined by α-1,4glucosidic bonds, 7% of glucosyl residues are joined by α-1,6glucosidic bonds 2. About each ten glucosyl residues, a branch occurs. More branches , higher solubility. 3. Each chain ends in a reduced terminal, benefiting the degradation by enzyme 目录 1. Glycogen Formation ( glycogenesis ) Definition of glycogenesis It is the process to synthesize glycogen from glucose. Synthesis sites in organism Organ sites:mainly in liver and muscle Cellular site:cytoplasm Pathway of glycogen synthesis (1) Glucose is phosphorylated to G-6-P ATP Glucose ADP Glucose-6-phosphate hexokinase; glucokinase(liver) (2) G-6-P turn to G-1-P G-6-P Phosphoglucomutase G-1-P Phosphogluco mutase Glucose-6-phosphate Glucose-1-phosphate (3) G-1-P turn to UDPG CH2OH H H OH O H HO O H + H P P P uridine P UTP OH G-1-P CH2OH H H OH UDPGpyrophosphorylase HO PPi O H H O H P P uridine 尿苷 OH ( uridine diphosphate glucose , UDPG ) 2Pi+energy * UDPG can be seen as active glucose donor Uridine diphosphate glucose , UDPG structure Active glucose 制作:吴耀生 目录 (4) Formation of α-1,4-glucosidic bond Gn + UDPG glycogen synthase Gn+1 + UDP One more glucose is added to the glycogen primer or glycogen molecule UDP ATP Nucleoside diphosphate kinase UTP ADP (5) The formation of branch of glycogen α-1,4 glycosidic bond α -1,4-糖苷键 分 支 酶 (branching enzyme) α-1,6 glycosidic bond α-1,6-糖苷键 目录 Glycogen synthesis UDP-glucose pyrophosphorylase G G-6-P hexokinase G-1-P Phosphoglucomutase UDP-G + PPi UTP Glycogen synthase Gn Gn+1 Enzymes -UDP-glucose pyrophosphorylase -Glycogen synthase (key enzyme) -Branching enzyme [amylo-(1-41-6) Transglycosylase] Notes It needs primer before the synthesis of Gn 制作:吴耀生 目录 2. Glycogen Degradation ( Glycogenolysis ) * Definition of glycogenolysis Generally, it refers the process of hepatic glycogen hydrolyzed to release glucose. * Cellular site:in cytoplasm (1) Glycogen suffer phosphorolysis Gn+1 phosphorylase 制作:吴耀生 Gn + G-1-P 目录 (2) Debranching enzyme ① transfer glycosyl residues ② hydrolyzing -1,6glycosidic bond (debranching enzyme) phosphorylase transferase α-1,6 glucosidase 目录 (3) G-1-P turn to G-6-P Glucose-1phosphate Glucose-6phosphate Phosphoglucomutase (4) G-6-P is hydrolyzed to yield glucose glucose-6-phosphaste Glucose glucose-6-phosphatase (liver,kidney) Attention: there are no glucose-6-phosphatase in skeleton muscle, so glycogen couldn’t be used to replenish blood sugar because of no free G released into blood from muscle glycogen. Summary for glycogenesis and glycogenolysis (1) Reaction site:in cytoplasm (2) The fates of G-6-P metabolism G(to replenish blood sugar) 6-phosphogluconolactone (into PPP) G-6-P F-6-P (into glycolysis) G-1-P UDPG glucuronate (into glucuronate pathway) Gn(to synthesize glycogen) The total chart for glycogenesis and glycogenolysis Gn+1 UDP Gn Pi Gn synthase UDPG PPi Gn Phosphorylase UDPG pyrophosphorylase UTP G-1-P Phosphoglucomutase Glucose-6-phosphatase(liver) G-6-P G Hexo(gluco)kinase 3. The Regulation of Glycogensis and Glycogenolysis Key enzyme ① Glycogenesis:Gn synthase ② Glycogenolysis:Gn phosphorylase The important characters of these two enzymes: * The covalent modification and allosteric regulation as rapid regulation models * There are two types of enzyme with active or inactive (low active) forms interconverting mutually through phosphorylation or dephosphorylation 3.1 Phosphorylase ATP Phosphorylase b kinase Phosphorylase b (dephosphorylated, inactive ) Pi ADP Phosphorylase a ( phosphorylated, active ) Protein phosphatase I 3.2 Glycogen Synthase Protein phosphatase Glycogen synthase b (phosphorylated, inactive ) ADP Pi Glycogen synthase a (dephosphorylated, inactive ) Protein kinase A ATP hormones(glucagon 、epinephrine)+ receptor Adenyly cyclase (inactive) Adenyly cyclase (active) ATP cAMP Pi Phosphorylase b kinase PKA PKA (inactive) (active) Phosphoprotein phosphatase-1 Phosphorylase b kinase-P – Gn synthase Gn synthase-P active Pi inactive Phosphorylase b Phosphorylase a-P inactive Phosphoprotein Phosphatase-1 Pi active Phosphoprotein phosphatase-1 – – Phosphoprotein Phosphatase inhibitor-P PKA(active) Phosphoprotein Phosphatase inhibitor 4. The Significance of Glycogenesis and Glycogenolysis After a meal, the excessive glucose will store in liver as glycogen. After fasting, liver glycogen is degraded into glucose and released to blood for keeping the blood sugar level Liver glycogen can store energy and regulate the blood sugar level. 制作:吴耀生 目录 5. glycogen storage diseases Glycogen storage diseases are a group of inherited disorders characterized by deposition of an abnormal type or quantity of glycogen in some tissues. Section Six Gluconeogenesis * Definition Gluconeogenesis is a process to synthesize glucose or glycogen from noncarbohydrate precursors. * Cellular site: In cytoplasm and mitochondria in liver or kidney. * Raw material Glycerol, glucogenic amino, lactate, and other organic acids. Glu 1.The Basic Process of Gluconeogenesis ATP ADP G-6-P F-6-P ATP ADP F-1,6-2P 3-GAP DHAP NAD+ NADH+H+ 1,3-DPGA ADP ATP 3-PGA 2-PGA PEP ADP ATP Pyruvate The main pathway for gluconeogenesis is essentially a reversal of glycolysis, but there are three energy barriers obstructing a simple reversal of glycolysis 1.1 The Conversion of Pyruvate to Phosphoenolpyruvate (PEP) ATP pyruvate CO2 ADP+Pi GTP GDP oxaloacetate ① PEP ② CO2 ① Pyruvate carboxylase, coenyzme is biotin. Reaction occurs in mitochondria. ② Phosphoenol pyruvate carboxykinase (PEP carboxykinase ) in mitochondria and cytoplasm Process of Gluconeogenesis 目录 PEP cytoplasm GDP + CO2 PEP carboxykinase GTP Aspartate Oxaloacetate Malate Malate Aspartate NAD+ α-ketoglutarate NADH + H+ Glutamate Oxaloacetate ADP + Pi ATP + CO2 mitochondria Pyruvate carboxylase Pyruvate Pyruvate 1.2 F-1,6-DP turns to F-6-P Pi F-6-P F-1,6-DP Fructose-1,6-diphosphatase 1.3 G-6-P is hydrolyzed to glucose Pi G-6-P glucose-6-phosphatase Glucose 2. The Cori Cycle (Lactate cycle ) LIVER MUSCLE Glucose Glucose Gluconeogenesis Pyruvate Lactate Dehydrogenase Lactate Blood Glycolysis Pyruvate NADH NADH +H+ Lactate Dehydrogenase NAD+ Lactate 制作:吴耀生 +H+ NAD+ 目录 The significances of Cori Cycle 1) To avoid the lose of lactate and get the reuse of muscle lactate ( lactate in muscle could be used to synthesize glucose) 2) To prevent the build up of lactate in muscle Glucogen in muscle Glucose in blood gluconeogenesis glycolysis Lactate in blood Synthesis of glucogen Glucogen in liver Degradation of glucogen Glucogen in muscle 制作:吴耀生 目录 3. Regulation of Gluconeogenesis G-6-Pase G-6-P G ADP F-1,6-DPase-1 HK Pi F-1,6-DP ADP Pi ATP F-6-P F-1,6-DPase-1 ATP ADP+Pi Py carboxylase GTP PEP carboxylkinase oxaloacetate GDP+Pi CO2+ATP PEP pyruvate ADP Py kinase ATP +CO2 4. The Significance of Glyconeogenesis (1) To maintain blood glucose levels stable during starvation or during vigorous exercise. It is more important for the functions of brain or erythrocytes. (2) To replenish liver glycogen (3) To regulate acid-base equilibrium. Section Seven Blood Glucose and Its Regulation 1. Blood Sugar Level * Blood sugar refers the level of glucose in blood. Normal blood sugar concentration: 3.89~6.11mmol/L The income and outcome of blood sugar Dietary supply Digestion and absorption Oxidation CO2 + H2O Gn synthesis degradation Liver glycogen glyconeogenesis Noncarbohydrates Blood sugar PP Pathway liver (muscle) Gn Other sugar Lipid, AA synthesis Fat, AA 2. Regulation of Blood Glucose Concentration * Mainly, the regulation depends on hormones Hormones Decrease blood sugar: insulin Increase blood sugar: glucagon, glucocorticoids, epinephrine ( adrenalin ) 2.1 Insulin —— the unique a hormone to decrease blood level in body Mechanism of insulin action ① Effects on membrane actively transport ② Effects on glucose utilization ③ Effects on gluconeogenesis ④ Decrease lipolysis and stimulates the uptake of neutral AA into muscle for protein biosynthesis 2.2 Glucagon ——One of the hormones to increase blood sugar level Mechanism of glucagon action ① Improve glycogenolysis, inhibit glycogen synthesis ② Inhibit glycolysis, improve gluconeogenesis ③ Activate the triacylglyceride mobilization 2.3 Epinephrine (adrenalin ) ——A hormone for increasing blood sugar in stress Target tissues: liver and muscle. To stimulate glucogenolysis to produce glucose in liver and lactate in muscle; To stimulate gluconeogenesis; To enhance the transport of glucogenic amino acids to liver for gluconeogenesis 2.4 Glucocorticoids ——One of the hormones to increase blood sugar Mechanism of glucocorticoid action To stimulate the gluconeogenesis To inhibit the utilization of glucose by inhibiting pyruvate dehydrogenase complex To promote lipolysis for increasing free fatty acids level in blood 3. Abnormal Blood Sugar Level 3.1 Hyperglycemia Definition of hyperglycemia It is termed hyperglycemia when the blood sugar concentration in fasting is higher than 7.22~7.78 mmol/L in clinic. Renal threshold for glucose When blood sugar conc. is higher than 8.89 ~10.00 mmol/L, it is over the ability of renal tubular to reabsorb glucose, resulting in glucose appearing in urine. Therefore, this blood sugar level is termed renal threshold for glucose. The case which glucose presents in urine is called glycosuria The reasons for glycosuria: Emotional, alimentary, symptomatic and renal glycosuria, insulin absolutely deficiency or relatively deficiency, etc. 制作:吴耀生 目录 Diabetes mellitus, DM There two types for diabetes mellitus Ⅰtype ---- insulin-dependent diabetes mellitus Ⅱtype ---- non-insulin dependent diabetes mellitus 3.2 hypoglycemia Definition of hypoglycemia It refers the case when blood sugar conc. in fasting is lower than 3.33~3.89 mmol/L The impact of hypoglycemia to body The functions of brain cells would be affected, then various symptoms such as be light in the head swirl, accidie, atony, heartthrob, more severely coma would appear. The pathogeny of hypoglycemia ① Relate to pancreas (the excessive of islet β-cell functions, or the deficiency of islet αcell functions ) ② Relate to liver(liver cancer, glycogen storage disease, etc) ③ abnormal secretory action ( pituitary function deficiency, adrenal gland cortex function deficiency, etc. ) ④ tumor ⑤ starvation, or unavailable to take food The disease related to the metabolism of galactose---Galactosemia What’s it: It is a genetic disease caused by an inability to convert galactose to glucose. Toxic substances accumulate such as galactitol, formed by the reduction of galactose Symptom: fail to thrive, vomit or diarrhea after drinking milk, and often enlarged liver and jaundice. The formation of cataracts , mental retardation and an early death Reasons: due to a deficiency of the galactose-1phosphate uridylyl transferase hence cannot metabolize galactose. Treating: by prescribing a galactose-free diet which causes all the symptoms to regress except mental retardation which may be irreversible. 制作:吴耀生 目录 Disease cases 1. Diabetes mellitus (糖尿病) 2. Hypoglycemia (低血糖症) 3. Galactosemia (半乳糖血症) 制作:吴耀生 目录 Concepts 1 Glycolysis 2 Gluconeogenesis 3 The Cori Cycle ( lactate cycle ) 4 Pentose Phosphate Pathway 5 Glycogen 制作:吴耀生 目录 Questions 1 As you know, which kinds of sugar in daily life belong to monosaccharide? Which ones belong to disaccharide? Which ones belong to polysaccharide? 2 What are the key enzymes for the glycolysis pathway? The location in cells? 3 Which kinds of substances can be turned to glucose through gluconeugensis pathway? 制作:吴耀生 目录 4 How many ATP could be produced when one of molecule of glucose be metabolized by glycolysis pathway or by aerobic oxidization pathway? 5 What are the significances of pentose phosphate pathway ? 6 In which organ, glycogen can be degraded to glucose ? Why? 7 What is the key enzyme for glycogen synthesis or glycogen degradation, respectively? 制作:吴耀生 目录 Thank you 制作:吴耀生 目录