Endocrine Regulation Of Glycogen Metabolism PDF

2 2. ENDOCRINE REGULATION 1  2. CARBOHYDRATE METABOLISM I – CONTENT – VIII. Glycogenolysis XI. Receptors and tissue-specific outcomes Regulation of glycogen phosp...

2 2. ENDOCRINE REGULATION 1  2. CARBOHYDRATE METABOLISM I – CONTENT – VIII. Glycogenolysis XI. Receptors and tissue-specific outcomes Regulation of glycogen phosphorylase a and b Epinephrine and a-adrenergic receptor Clinical correlations Epinephrine and b-adrenergic receptor von Gierske’s disease (Type I) Glucagon and glucagon receptor McArdle’s disease (Type V) XII. Tissue-specific carbohydrate metabolism Fanconi-Bickel’s syndrome (Type XVI) Erythrocytes IX. Glycogenesis Brain Regulation of glycogen synthase D and I Muscle X. Endocrine Regulation of glycogen metabolism Adipose Tissue Epinephrine/Glucagon Liver cAMP- and PKA-driven pathways Integration with co-regulatory enzymes of glycogen metabolism Insulin The insulin receptor Insulin signaling on glycogen metabolism Integration with co-regulatory enzymes of glycogen metabolism 2  2. CARBOHYDRATE METABOLISM II – LEARNING OBJECTIVES – Evaluate the co-regulatory mechanisms of glycogenesis and glycogenolysis based on their two key enzymes Analyze the epinephrine regulation of glycogen metabolism based on the three main actions of PKA Integrate the epinephrine regulation into the co-regulatory mechanisms of glycogenesis and glycogenolysis Recognize the functional aspects of the insulin receptor and analyze the effects of insulin on glycogen metabolism Integrate the insulin regulation into the co-regulatory mechanisms of glycogenesis and glycogenolysis Identify the genetic deficiencies inherent in glycogen metabolism and their outcomes Distinguish the major pathways of carbohydrate metabolism in a tissue-specific manner 3  WHY METABOLISM OF CARBOHYDRATES AND LIPIDS? SIGNIFICANCE: STARVE-FEED CYCLE DIABETES OBESITY ATHEROSCLEROSIS CELL SIGNALING ALZHEIMER’S DISEASE [lactate] insulin [pyruvate] glucagon HYPOXIA b cells a cells Pancreas 4  VIII. GLYCOGENOLYSIS Glycogen Anabolism Glycogenolysis Glycogenesis Pentose Phosphate GLUCOSE Ribose-5-P Pathway Glycolysis Gluconeogenesis Catabolism Pyruvate 5  VIII. GLYCOGENOLYSIS Glycogen is the major storage form of carbohydrate in animals (corresponds to starch in plants). The function of glycogen in muscle is to act as a readily available source of glucose for glycolysis within the muscle itself. Liver glycogen is largely concerned with export of glucose for maintenance of glycemia. Glycogen is degraded to glucose units by the activity of glycogen phosphorylase, that catalyzes by phosphorolysis the release of glucose-1P from glycogen ([glucose]n): [glucose]n + Pi → [glucose]n–1 + glucose-1P Phosphoglucomutase catalyzes the conver- 6 CH 2OH 6 CH 2OH 6 CH 2OH 6 CH 2OH 5 5 5 5 sion of glucose-1P to glucose-6P, which 4 1 4 1 4 1 4 1 O O O enters the glycolytic pathway. 3 2 3 2 3 2 3 2 [glucose]n 6 CH 2OPO3 2– 6 CH 2OH HPO42– 5 5 glycogen phospho- 1 phosphorylase 4 4 glucomutase 3 2 1 3 2 OPO32– glucose-6P glucose-1P 6 CH 2OH 6 CH 2OH 6 CH 2OH 5 5 5 1 1 1 4 4 O O 3 2 3 2 3 2 6 [glucose]n–1  VIII. GLYCOGENOLYSIS Glycogen phosphorylase occurs in two forms: the active form or glycogen phosphorylase–a and the inactive form or glycogen phosphorylase–b. Phosphorylase–a consists of four subunits: each subunit is phosphorylated. Protein phosphatase 1 removes the phosphate groups of glycogen- gen phosphorylase-a to yield glyco- 6 CH OH 2 6 CH OH 2 6 CH 2OH 6 CH 2OH 5 5 5 5 1 1 1 1 [glucose]n gen phosphorylase–b, which consists 4 4 4 4 O O O of two dimers and is converted back 3 2 3 2 3 2 3 2 protein phosphatase 1 to glycogen phosphorylase–a by 4 H2O phosphorylase kinase. 4 Pi HPO42– P P 6 CH 2OH 5 glycogen 1 phosphorylase 4 P phosphorylase b P OPO3 2– phosphorylase a 3 2 4 ADP glucose-1P 4 ATP 2– phosphorylase kinase 6 CH 2OH 6 CH 2OPO3 5 5 1 phospho- 1 6 CH 2OH 6 CH 2OH 6 CH 2OH 4 4 5 5 5 glucomutase 1 1 1 [glucose]n–1 3 2 OPO32– 3 2 4 4 glucose-1P glucose-6P O O 3 2 3 2 3 2 7  VIII. GLYCOGENOLYSIS Fates of Glucose-6P from Glycogen Metabolism in Muscle and Liver Glucose-6-phosphate from glycogen and by the action of glycogen phosphorylase and phosphoglucomutase has different fates depending on whether glucose-6P is in liver or muscle. Because liver contains glucose-6-phosphatase, glucose is dephosphorylated and exported into plasma. P P Muscle does not contain glucose-6-phosphatase, hence, glucose-6P is converted via glycolysis to P P lactate. glycogen phosphorylase a [glucose]n [glucose]n–1 Pi glucose-1P phospho- glucomutase lactate glucose-6P glucose glycolysis glucose-6P phosphatase Muscle Liver 8  VIII. GLYCOGENOLYSIS — SUMMARY — Pi H 2O [glucose]n protein phosphatase 1 phosphorylase phosphorylasebb Pi P b a phosphorylase a Glu-1P phosphorylase kinase [glucose]n–1 ATP ADP 9  VIII. GLYGENOLYSIS – CLINICAL CORRELATIONS – Type I or von Gierke’s disease: the activity of glucose-6- phosphatase is either extremely low or entirely absent in liver, intestinal mucosa, and kidney. This disease is characterized by large amounts of unavailable glycogen in liver and kidney and by hypoglycemia. Hypoglycemia is a consequence of the glucose-6-phosphatase deficiency, the enzyme required to obtain glucose from liver glycogen and gluconeogenesis; lactic acidemia occurs because liver cannot use lactate for glucose synthesis. Glucose-6-Pase glucose liver X glucose glucose Gluconeogenesis Glycolysis pyruvate pyruvate lactate lactate muscle lactate 10  VIII. GLYCOGENOLYSIS – CLINICAL CORRELATIONS – Type V or McArdle’s disease consists of a deficiency of phosphorylase activity in muscle. Patients exhibit markedly diminished tolerance to exercise and painful muscle cramps, because muscle glycogen stores are not available to the exercising muscle. Muscles are likely damaged because of the inadequate energy supply and glycogen accumulation. 11  VIII. GLYCOGENOLYSIS – CLINICAL CORRELATIONS – [GLUCOSE]n Type XI or Fanconi-Bickel syndrome consists of a deficiency of GLUT2; hence, liver cannot be Pi GLYCOGEN PHOSPHORYLASE [GLUCOSE]n–1 involved in regulation of glycemia because it cannot release glucose into the bloodstream. The GLUCOSE-1P disease proceeds with accumulation of glycogen PHOSPHOGLUCO- and severe hypoglycemia. Because this is a genetic MUTASE disease, treatment is only of symptoms through GLUCOSE-6P adequate diets. H 2O GLUCOSE-6- PHOSPHATASE Pi Fanconi-Bickel syndrome X GLUT2 GLUCOSE 12  IX. GLYCOGENESIS Glycogen Anabolism Glycogenolysis Glycogenesis Pentose Phosphate GLUCOSE Ribose-5-P Pathway Glycolysis Gluconeogenesis Catabolism Pyruvate 13  IX. GLYCOGEN SYNTHESIS: GLYCOGENESIS Overview The biosynthesis of glycogen takes place in three sequential steps: a. Isomerization of glucose-6-phosphate to glucose-1-phosphate b. Activation of glucose-1-phosphate to UDP-glucose c. Transfer of the glucosyl residue in UDP-glucose to an amylose chain 14  IX. GLYCOGENESIS The Three Sequential Steps of Glycogenesis a. Isomerization of glucose-6-phosphate to glucose-1-phosphate is catalyzed by phosphoglucomutase, a freely reversible reaction: 6 CH 2– 6 CH 2OPO3 2OH 5 5 1 phospho- 1 4 4 glucomutase 3 2 3 2 OPO32– glucose-6P glucose-1P b. Activation of glucose-1-P to UDP-glucose – The glucosyl donor (glucose- 1P) for glycogen synthesis is activated as UDP-glucose in a reaction catalyzed by glucose-P-uridyl transferase: Glucose-1P + UTP → UDP-glucose + PPi O O BASE BASE N N O N O N O O O O O || || || || || –O—P—O—P—O—P—O—CH 2 O glucose –O—P—O—P—O—P—O—CH 2 O | | | | | O– O– O– O– O– HO OH HO OH RIBOSE RIBOSE UMP UDP-glucose UDP UTP 15  IX. GLYCOGENESIS c. Transfer of the glucosyl reside in UDP-glucose to an amylose chain – The glucosyl group of UDP-glucose is transferred to the terminal glucose residue at the non-reducing end of an amylose chain to form an a(1→4) glycosidic linkage. The reaction is catalyzed by glycogen synthase 6 CH 2OH 6 CH 2OH 6 CH 2OH 6 CH 2OH 1 1 1 1 4 4 4 4 O O O [glucose]n CH2OH 4 O—UDP UDP-Glucose glycogen synthetase UDP 6 CH 2OH 6 CH 2OH 6 CH 2OH 6 CH 2OH 1 1 1 1 4 4 4 4 O O O [glucose]n+1 16  IX. GLYCOGENESIS Glycogen synthase occurs in two forms: the phosphorylated form is inactive by itself, although it is allosterically stimulated by glucose-6-phosphate and is, therefore, called D or Dependent form (Glycogen synthase D). Glycogen synthase D can be converted to the active form, glycogen synthase I, by protein Pi phosphatase 1 (I for Indepen- H2O dent form, because it does not [glucose]n protein require glucose-6P as an allo- phosphatase 1 steric regulator). Conversely, glycogen synthase D UDP (inactive) P glycogen synthase I can be Glu-6P I D inactivated to glycogen synth- UDP-Glucose glycogen synthase I (active) cAMP ase D by protein kinase A, protein kinase A (PKA), which, in turn, is allo- (PKA) [glucose]n–1 sterically activated by cAMP ATP (cyclic AMP ). ADP 17  IX. GLYCOGENESIS — SUMMARY — Pi H2O [glucose]n protein phosphatase 1 UDP glycogen synthase D (inactive) P Glu-6P I D UDP-Glucose glycogen synthase I (active) cAMP protein kinase A (PKA) [glucose]n–1 ATP ADP 18  IX. REGULATORY STEPS OF GLYCOGENOLYSIS AND GLYCOGENESIS Glycogen phosphorylase and glycogen synthase are the regulatory enzymes in glycogenolysis and glycogenesis, respectively. The enzymes are activated / inactivated by mechanisms involving phosphorylation / dephosphorylation reactions that are critical for the regulation of cell signaling pathways. Pi Pi H2O H2O [glucose]n protein protein phosphatase phosphatase 1 1 UDP glycogen synthase D phosphorylase b P Pi (inactive) P a Glu-6P b UDP-Glucose I D phosphorylase a glycogen synthase I Glu-1P (active) cAMP phosphorylase protein kinase A kinase (PKA) [glucose]n–1 ATP ATP ADP ADP 19 OVERVIEW OF THE MAIN CARBOHYDRATE METABOLIC PATHWAYS [GLUCOSE]n GLYCOGENESIS GLYCOGENOLYSIS GLYCOGEN GLYCOGEN PHOSPHORYLASE SYNTHASE ANABOLISM CATABOLISM GLUCOSE-1-P GLUCOSE-6-P GLUCONEOGENESIS GLYCOLYSIS PHOSPHOFRUCTO PHOSPHOFRUCTO KINASE PHOSPHATASE PYRUVATE 20  X. ENDOCRINE REGULATION OF GLYCOGEN METABOLISM Liver has a large capacity for storing glycogen; in a well-fed individual, the content of glycogen in liver accounts for ~10% of the liver weight. Liver glycogen functions as a glucose reserve in order to maintain blood glucose concentrations, thus furnishing fuel to other tissues Muscle stores less glycogen (~1% of total muscle weight). Muscle stores glycogen as a fuel reserve for the production of energy to support muscle work. 21  X. ENDOCRINE REGULATION OF GLYCOGEN METABOLISM Hyperglycemic and Hypoglycemic Hormones Superimposed on the allosteric controls over glycogen synthase and glycogen phosphorylase, is another set of controls involving regulation by hormones, particularly by Epinephrine and Glucagon Insulin Basic principles: The responsive target cells for any hormone contain specific hormone receptors, which are specialized proteins capable of binding the hormone molecule with high specificity and affinity. The receptors for epinephrine, glucagon, and insulin are located on the cell surface. The binding of the hormone to its specific receptor causes the formation of an intracellular messenger molecule, which stimulates or depresses some biochemical activity of the target tissue. 22  X. ENDOCRINE REGULATION OF GLYCOGEN METABOLISM EPINEPHRINE Secretion of epinephrine by the adrenal medulla into the blood triggers a prominent response in target organs, which consists of an increased rate of breakdown of glycogen in the muscles to yield lactate and in the liver to yield blood glucose, along with inhibition of glycogen synthesis in the latter organ. GLYCOGEN GLUCOSE-6P GLUCOSE EPINEPHRINE GLYCOGEN GLUCOSE-6P LACTATE 23  IX. REGULATORY STEPS OF GLYCOGENOLYSIS AND GLYCOGENESIS Glycogen phosphorylase and glycogen synthase are the regulatory enzymes in glycogenolysis and glycogenesis, respectively. The enzymes are activated / inactivated by mechanisms involving phosphorylation / dephosphorylation reactions that are critical for the regulation of cell signaling pathways. Pi Pi H2O H2O [glucose]n protein protein phosphatase phosphatase 1 1 UDP glycogen synthase D phosphorylase b P Pi (inactive) P a Glu-6P b UDP-Glucose I D phosphorylase a glycogen synthase I Glu-1P (active) cAMP phosphorylase protein kinase A kinase (PKA) [glucose]n–1 ATP ATP ADP ADP 24  X. ENDOCRINE REGULATION OF GLYCOGEN METABOLISM receptor epinephrine EPINEPHRINE a. Binding of epinephrine to the b-adrenergic AC plasma activated adenylate membrane receptor in the plasma membrane of liver or cyclase cAMP ATP muscle cells leads to the activation of a adenylate plasma membrane adenylate cyclase that cyclase ATP AMPc + PPi catalyzes the conversion of ATP into cyclic NH2 AMP (cAMP) and pyrophosphate (PPi). The N N binding of glucagon to the glucagon receptor proceeds by the same mechanism, N N i.e., activation of adenylate cyclase and O—CH2 O formation of the secondary messenger, cAMP. O –— P O OH || O 25  X. ENDOCRINE REGULATION OF GLYCOGEN METABOLISM EPINEPHRINE b. cAMP exerts its effects mainly by activating cAMP C R a cyclic AMP-dependent protein kinase: inactive protein kinase A (PKA). The activation of PKA requires binding of cAMP to the R cAMP PKA regulatory subunit (R) of PKA, thereby active dissociating it from the catalytic subunit (C). 26  X. ENDOCRINE REGULATION OF GLYCOGEN METABOLISM EPINEPHRINE c. Once activated, PKA modulates glycogen metabolism in a concerted manner that affects three pathways: Stimulation of glycogenolysis by facilitating the conversion of phosphorylase-b to the active form phosphorylase-a. Inhibition of glycogenesis by facilitating the conversion of glycogen synthase I to the inactive glycogen synthase D. Stimulation of glycogenolysis and inhibition of glycogenesis upon inhibition of protein phosphatase I (an enzyme shared by both pathways, glycogenolysis and glycogenesis) 27 Glycogenolysis PKA Glycogenesis ❶ ❷ Inhibitor 1 X. ENDOCRINE REGULATION OF GLYCOGEN METABOLISM ❸ EPINEPHRINE Protein Phosphatase 1 Stimulation of glycogenolysis by facilitating the conversion of phosphorylase-b to the active phosphorylase-a. The active PKA stimulates the conversion of dephosphophosphorylase kinase (inactive form) into phosphophosphorylase kinase (active form). The reaction reaction requires Ca++. The active phosphorylase kinase catalyzes the conversion of phosphorylase–b into phosphorylase–a. Phosphorylase–a, in turn, catalyzes the breakdown of PROTEIN KINASE A glycogen ([glucose]n) into glucose–1P, which follow- (active) 4 ATP ing isomerization is converted into glucose-6P. PKA C ATP PHOSPHORYLASE b OH PKA OPO3 2– Ca++ P Ca++ 4 ADP ATP dephospho- DEPHOSPHO– ADP PHOSPHO– ADP P P PHOSPHORYLASE phosphorylase PHOSPHORYLASE KINASE kinase KINASEphospho- (inactive) (inactive) (active) phosphorylase kinase (active) P P PHOSPHORYLASE a 28  Stimulation of glycogenolysis by facilitating the conversion of phosphorylase-b to phosphorylase-a b-adrenergic epinephrine 10–9 M receptor AC ATP cAMP phosphorylase-b PKA Dephospho- phosphorylase Ca2+ Phosphorylase kinase kinase [glucose]n phosphorylase-a glucose-1P glucose-6P glucose-6 phosphatase 10–3 M GLUCOSE 29  Stimulation of glycogenolysis by facilitating the conversion of phosphorylase-b to phosphorylase-a b-adrenergic epinephrine receptor AC ATP cAMP phosphorylase-b PKA Dephospho- phosphorylase Ca2+ Phosphorylase kinase kinase [glucose]n phosphorylase-a glucose-1P lactate pyruvate glycolysis glucose-6P LACTATE 30 Glycogenolysis PKA Glycogenesis ❶ ❷ Inhibitor 1 ❸ X. ENDOCRINE REGULATION OF GLYCOGEN METABOLISM Protein Phosphatase 1 EPINEPHRINE Inhibition of glycogen synthesis by epinephrine is achieved by the PKA-mediated phosphorylation of glycogen synthase I (active) to glycogen synthase D (inactive). The inhibition of glycogen synthase is therefore brought about by a chain of events triggered by the same stimulus that causes acceleration of glycogen breakdown to yield blood glucose. Epinephrine not only stimulates glycogen breakdown but also inhibits glycogen synthesis in the liver, thus directing all available glucose residues and precursors into the production of free blood glucose PKA Glycogen Glycogen Synthase Synthase I D P active inactive non-phosphorylated phosphorylated 31 Inhibition of glycogenesis by facilitating the conversion of glycogen synthase I to glycogen synthase D b-adrenergic epinephrine receptor AC ATP cAMP PKA PKA Glycogen Glycogen Synthase Synthase I D P active inactive non-phosphorylated phosphorylated 32 Glycogenolysis PKA Glycogenesis ❶ ❷ EPINEPHRINE Inhibitor 1 ❸ Stimulation of glycogenolysis and inhibition of phosphorylase b glycogenesis upon inhibition of protein phosphatase synthase I Protein glycogen glycogen Phosphatase 1 I. Protein phosphatase 1 catalyzes the conversion phosphatase protein phosphorylase-a → phosphorylase b (thus inactivat- phosphorylase a 1 synthase D glycogen glycogen ing glycogen breakdown) and the conversion glycogen synthase D → glycogen synthase I (thus stimulating glycogen biosynthesis). Protein phosphatase I glycogen phosphorylase b is inhibited by inhibitor 1, that exists under two forms: the phos- glycogen phosphorylase a phorylated- and the dephosphorylated forms. The phosphorylated inhibitor 1 form of inhibitor 1 blocks the protein phosphatase 1 protein inhibitor 1 inhibitor 1 activity. The phosphorylation of inhibitor 1 is under phosphatase P 1 ATP hormonal control, because it is phosphorylated by P ADP ADP PKA and, therefore, its degree of phosphorylation glycogen ADPis synthase D dependent on the cellular concentration of cAMP. PKA glycogen p ATP ATP synthase I inhibitor 1 inhibitor 1 inhibitor 1 ATP 33 Stimulation of glycogenolysis and inhibition of glycogenesis upon inhibition of protein phosphatase I b-adrenergic epinephrine receptor AC ATP cAMP glycogen phosphorylase b glycogen phosphorylase a PKA protein inhibitor 1 inhibitor 1 phosphatase 1 ATP P glycogen ADP synthase D glycogen synthase I 34  X. ENDOCRINE REGULATION OF GLYCOGEN METABOLISM – SUMMARY EPINEPHRINE – b-adrenergic epinephrine receptor AC ATP DEPHOSPHO- cAMP GLYCOGEN PHOSPHORYLASE SYNTHASE I KINASE (active) (inactive) PHOSPHATASE PROTEIN Ca2+ 1 PHOSPHORYLASE-b PKA (inactive) PHOSPHATASE PROTEIN PHOSPHO- GLYCOGEN glycogen PHOSPHORYLASE SYNTHASE D 1 KINASE (inactive) (active) PHOSPHORYLASE-a (active) INHIBITOR 1 INHIBITOR 1 (inactive) (active) glucose-1P 35  X. REGULATORY STEPS OF GLYCOGENOLYSIS AND GLYCOGENESIS Glycogen phosphorylase and glycogen synthase are the regulatory enzymes in glycogenolysis and glycogenesis, respectively. The enzymes are activated / inactivated by mechanisms involving phosphorylation / dephosphorylation reactions that are critical for the regulation of cell signaling pathways. Pi Pi H2O H2O [glucose]n protein protein phosphatase phosphatase 1 1 UDP glycogen synthase D phosphorylase b P Pi (inactive) P a Glu-6P b UDP-Glucose I D phosphorylase a glycogen synthase I Glu-1P (active) cAMP phosphorylase protein kinase A kinase (PKA) [glucose]n–1 ATP ATP EPINEPHRINE EPINEPHRINE ADP ADP 36  X. ENDOCRINE REGULATION OF GLYCOGEN METABOLISM Hyperglycemic and Hypoglycemic Hormones Superimposed on the allosteric controls over glycogen synthase and glycogen phosphorylase, is another set of controls involving regulation by hormones, particularly by Epinephrine and Glucagon Insulin Basic principles: The responsive target cells for any hormone contain specific hormone receptors, which are specialized proteins capable of binding the hormone molecule with high specificity and affinity. The receptors for epinephrine, glucagon, and insulin are located on the cell surface. The binding of the hormone to its specific receptor causes the formation of an intracellular messenger molecule, which stimulates or depresses some biochemical activity of the target tissue. 37  X. ENDOCRINE REGULATION OF GLYCOGEN METABOLISM INSULIN Insulin is secreted by the b cells of the islet of pancreas. The release of insulin from pancreas depends on the blood glucose concentration. When the blood glucose increases significantly above its normal level (80-90 mg/100 ml), insulin is secreted into the blood. The effect of insulin is a prompt reduction of blood glucose level due to: an enhancement of the transport of glucose from the blood across the plasma membrane of muscle and fat cells (facilitated by GLUTs). stimulation glycogenesis by favoring the conversion of glycogen synthase D (inactive) into glycogen synthase I (active). insulin differs from glucagon and epinephrine in that its binding to the target cell membrane does not cause an increase in cAMP 38  X. ENDOCRINE REGULATION OF GLYCOGEN METABOLISM THE INSULIN RECEPTOR The insulin receptor is an integral membrane –S–S– glycoprotein consisting of two a and two b Cysteine-rich domain chains joined by three disulfides bonds. The a a-chain a-chain chains are on the extracellular side of the membrane, whereas the b chains traverse the –S–S– –S–S– membrane. The a chains contain a cysteine-rich b-chain domain, whereas the b chains contain a tyrosine b-chain Plasma kinase domain. Membrane Tyrosine kinase The overall effects of insulin are rationalized in domain terms of the mechanism involving tyrosine kinase activity of the insulin receptor. 39  X. ENDOCRINE REGULATION OF GLYCOGEN METABOLISM BINDING OF INSULIN TO THE INSULIN RECEPTOR (IR) Upon binding of insulin the receptor becomes activated, i.e., the tyrosine kinase domain located on the cytosolic portion of the b chains phosphorylates itself (autophosphorylation). Thus, the activated insulin receptor is an enzyme that catalyzes the phosphorylation of tyrosine residues in target proteins. ACTIVE RECEPTOR PHOSPHORYLATES TYROSINE RESIDUES Insulin IN OTHER PROTEINS –S–S– –S–S– –S–S– –S–S– –S–S– –S–S– a-chain a-chain a-chain a-chain a-chain a-chain a-chain a-chain a-chain a-chain a-chain a-chain –S–S– –S–S– –S–S– –S–S– –S–S– –S–S– –S–S– –S–S– –S–S– –S–S– –S–S– –S–S– b-chain b-chain b-chain b-chain b-chain b-chain b-chain b-chain b-chain b-chain b-chain b-chain P P P P P P P P RECEPTOR INSULIN-BOUND PHOSPHORYLATED TYROSINE P TO RECEPTOR KINASE IN RECEPTOR Protein Protein CATALYTIC ACTIVITY (AUTOPHOSPHORYLATION) Protein Pr P OF TYROSINE KINASE Protein Protein DOMAIN IS SWITCHED 39  X. ENDOCRINE REGULATION OF GLYCOGEN METABOLISM THE INSULIN SIGNALING PATHWAY phosphorylase Once the insulin receptor is activated, its glycogen b phosphorylase b glycogenolysis Decreased autophosphorylation increases the capacity of phosphorylase glycogen phosphorylase a a tyrosine kinase to phosphorylate PKA PKA tyrosine Protein inhibitor residues on target 1 proteins, among inhibitor them a1 insulin P Phosphatase I glycogenesis protein target that stimulates ATP ATP ADP protein Increased ADP glycogen glycogen synthase D phosphatase 1. Activation of protein phos- glycogen synthase glycogen D synthase synthase I I phatase 1 leads to increased rates of glyco- genesis and decreased rates of glycogenolysis 41  X. REGULATORY STEPS OF GLYCOGENOLYSIS AND GLYCOGENESIS — INSULIN — Protein Phosphatase 1 is involved in the regulation of glycogenolysis and glycogenesis. Insulin stimulates protein phosphatase 1, thereby inhibiting the degradation of glycogen and activating the synthesis of glycogen. Pi Pi H2O INSULIN INSULIN H2O [glucose]n protein protein phosphatase phosphatase 1 1 UDP glycogen synthase D phosphorylase b P Pi (inactive) P a Glu-6P b UDP-Glucose I D phosphorylase a glycogen synthase I Glu-1P (active) cAMP phosphorylase protein kinase A kinase (PKA) [glucose]n–1 ATP ATP ADP ADP 42  X. REGULATORY STEPS OF GLYCOGENOLYSIS AND GLYCOGENESIS Glycogen phosphorylase and glycogen synthase are the regulatory enzymes in glycogenolysis and glycogenesis, respectively. The enzymes are activated / inactivated by mechanisms involving phosphorylation / dephosphorylation reactions that are critical for the regulation of cell signaling pathways. Pi Pi H2O H2O [glucose]n protein protein phosphatase phosphatase 1 1 UDP glycogen synthase D phosphorylase b P Pi (inactive) P a Glu-6P b UDP-Glucose I D phosphorylase a glycogen synthase I Glu-1P (active) cAMP phosphorylase protein kinase A kinase (PKA) [glucose]n–1 ATP ATP EPINEPHRINE EPINEPHRINE ADP ADP 43 XI. RECEPTORS, SECOND MESSENGERS, AND TISSUE-SPECIFIC OUTCOMES 44 XI. RECEPTORS, SECOND MESSENGERS, AND TISSUE-SPECIFIC OUTCOMES GLUCAGON AND EPINEPHRINE STIMULATE GLYCOGEN METABOLISM IN LIVER Glucagon is released from a cells of pancreas in response to low blood glucose levels; it binds to the glucagon receptors, located on the plasma membrane of hepatocytes and leads to the activation of adenylate cyclase and, consequently, activation glycogenolysis and inactivation of glycogenesis and to a rapid increase of blood glucose levels. Epinephrine is released into blood from the adrenal medulla in response to stress and interacts with b-adrenergic receptors in the hepatocyte plasma membrane to activate adenylate cyclase and outcomes similar to glucagon. 45 XI. RECEPTORS, SECOND MESSENGERS, AND TISSUE-SPECIFIC OUTCOMES EPINEPHRINE EFFECTS ON THE a-ADRENERGIC RECEPTOR IN THE LIVER The plasma membrane of hepatocytes has another binding protein for epinephrine, the a- adrenergic receptor. Interaction of epinephrine with this receptor leads to the formation of second messengers IP3 and DAG, generated in the plasma membrane by the action of phospholipase C on phosphatidylinositol-4,5- bisphosphate. IP3 stimulates Ca2+ release that activates phosphorylase kinase and inhibits phosphorylase. The consequences of epinephrine action are an increased release of glucose into the blood from the glycogen stored in liver. 46 XI. RECEPTORS, SECOND MESSENGERS, AND TISSUE-SPECIFIC OUTCOMES EPINEPHRINE STIMULATES GLYCOGENOLYSIS IN HEART AND SKELETAL MUSCLE Epinephrine stimulates glycogen degradation in heart and skeletal muscle upon binding to a b- adrenergic receptor: cAMP, the second messen- ger, activates glycogen glycogenolysis and inacti- vates glycogenesis. Glycolysis is also stimulated. These effects lead to formation of pyruvate. Skeletal muscle lacks glucose-6-phosphatase and as a consequence of the action of epinephrine on skeletal muscle lactate is released into blood and taken up by tissues (e.g., liver) that can synthesize glucose and regulate glycemia. 47 XI. RECEPTORS, SECOND MESSENGERS, AND TISSUE-SPECIFIC OUTCOMES NEURAL CONTROL OF GLYCOGEN METABOLISM IN SKELETAL MUSCLE Nervous excitation of muscle activity is mediated via the acetyl choline receptor and involves changes in Ca2+ concentrations through an initial membrane depolarization. The release of Ca2+ triggers muscle contraction. Changes in Ca2+ affect the activity of phosphorylase kinase and lead to activation of glycogen phosphorylase. The result is that more glycogen is converted to glucose-6-P so that more ATP can be produced to meet the greater energy demand of muscle contraction. 48 XI. RECEPTORS, SECOND MESSENGERS, AND TISSUE-SPECIFIC OUTCOMES 49  XI. RECEPTORS, SECOND MESSENGERS, AND TISSUE-SPECIFIC OUTCOMES INSULIN STIMULATES GLYCOGENESIS IN MUSCLE AND insulin insulin LIVER receptor An increase in blood glucose signals the release of insulin from the b cells of pancreas. Binding of insulin glycogen PrPase 1 PrPase 1 to its receptor promotes glucose utilization by GSD GSI P-a P-b promoting glycogenesis) and inhibiting glycogenolysis glucose-1P in muscle and liver. The glucose transporter in hepatocytes (GLUT2; high capacity) is insulin- glucose-6P insensitive, whereas glucose transport in muscle and adipocytes (GLUT4) is insulin-sensitive. Glycogenesis glucose is stimulated in both tissues upon activation of protein GLUT4 phosphatase-1, thus resulting in inhibition of glycogen plasma glucose membrane phosphorylase and stimulation of glycogen synthase. 50  XII TISSUE-SPECIFIC CARBOHYDRATE METABOLISM 51  XII. TISSUE-SPECIFIC CARBOHYDRATE METABOLISM RED BLOOD CELL After penetrating the plasma membrane by glucose mediated transport, glucose is metabolized GLUT mainly by glycolysis in erythrocytes. glucose Mature erythrocytes lack mitochondria; HK hence the end product of glycolysis is Pentose-P glucose-6P lactate, which is released from the red PPP glycolysis blood cells back into the plasma. pyruvate lactate Metabolism of glucose in red blood cells MCT via the pentose phosphate pathway provides lactate NADPH that is required to maintain glutathione levels 52  XII. TISSUE-SPECIFIC CARBOHYDRATE METABOLISM BRAIN glucose The brain, as the red blood cells, takes up GLUT glucose by mediated transport in an insulin- glucose independent manner (GLUT1 present in HK endothelial cells of the blood-brain barrier). Pentose-P glucose-6P PPP glycolysis Glycolysis in the brain yields pyruvate, which is then oxidized to CO2 and H2O via the pyruvate lactate lactate pyruvate tricarboxylic acid cycle (TCA). The pentose decarboxylation phosphate pathway is also quite active in acetyl-CoA brain and NADPH formed is used for reductive synthesis and to maintain TCA glutathione levels. GLUT4, however, present CO2 in neurons is an insulin-sensitive glucose transporter. 53  XII. TISSUE-SPECIFIC CARBOHYDRATE METABOLISM MUSCLE glucose Muscle and heart cells utilize glucose GLUT readily and its transport into these cells lactate glucose proceeds via the insulin-sensitive GLUT4. HK glycogenesis Glucose is metabolized via glycolysis to Pentose-P glucose-6P glycogen PPP glycolysis pyruvate and lactate. Pyruvate can be glycogenolysis oxidized to acetyl-CoA in mitochondria to pyruvate lactate MCT lactate generate considerable energy in the form of ATP. In contrast to brain and erythrocytes, acetyl-CoA muscle and heart cells can synthesize signi- ficant amounts of glycogen. Synthesis and TCA degradation of glycogen are important CO2 processes in these cells. 54  XII. TISSUE-SPECIFIC CARBOHYDRATE METABOLISM ADIPOSE TISSUE The transport of glucose into adipose tissue glucose occurs by the insulin-sensitive GLUT4. GLUT Pyruvate from glycolysis, can be oxidized by glucose HK the pyruvate dehydrogenase complex to acetyl- glycogenesis CoA. However, acetyl-CoA is primarily used Pentose-P glucose-6P glycogen PPP glycolysis glycogenolysis for the synthesis of fatty acids. Generation of pyruvate NADPH by the pentose phosphate pathway is pyruvate decarboxylation important in the adipocyte: NADPH is used for acetyl-CoA the de novo synthesis of fatty acids. Although synthesis and degradation of glycogen occurs in Fat the adipocyte, these processes are much more limited in this tissue than in muscle and heart. 55  XII. TISSUE-SPECIFIC CARBOHYDRATE METABOLISM LIVER Uptake of glucose by liver occurs independent glucose of insulin by means of a high capacity GLUT transport system (GLUT2). Glucose is used glucose in the pentose phosphate pathway for the Pentose-P HK glycogenesis synthesis of NADPH, which is required PPP glucose-6- glucose-6P glycogen for numerous reactions. glucose phosphatase glycogenolysis gluconeogenesis for glycogen storage (glycogen synthesis). glycolysis glucuronides for detoxification via the glucuronic acid pathway. pyruvate MCT lactate For the synthesis of fats via acetyl-CoA pyruvate decarboxylation yielded by pyruvate metabolism acetyl-CoA The liver is unique in that it also has the lipogenesis capacity to convert three carbon precursors, Fat such as lactate and alanine, into glucose by TCA gluconeogenesis. The glucose produced can is CO2 used to meet the metabolic needs of peripheral tissues. 56  CARBOHYDRATE METABOLISM GROUP PROJECT Description Derangements in carbohydrate metabolism occur because of genetic deficiencies of key enzymes, factors, transporters, or imbalances in aerobic/anaerobic metabolism resulting in a particular pathophysiology. 1. Lactic acidosis...................................................... 2. Hemolytic anemia................................................ pyruvate kinase 3. Hypoglycemia and premature infants.................. 4. Hypoglycemia and alcohol intoxication.............. 5. Wernicke-Korsakoff syndrome............................ 6. Drug hemolytic anemia........................................ 7. Pernicious anemia................................................ 8. Galactosemia........................................................ 9. Lactose intolerance.............................................. 10. Type I or von Gierke's disease............................. 11. Type V or McArdle's disease............................... 12. Type XI or Fanconi-Bickel's disease................... Steps 1 Complete the items above by adding the genetic deficiencies of key enzymes, factors, transporters, or imbalances in aerobic/anaerobic metabolism causing a particular pathophysiology (example in number 2 (hemolytic anemia)). 2 Explain the genetic deficiency inherent in 3 (hypoglycemia and premature infants) and whether or not the Cori cycle supports brain function under this condition. 3 Explain the genetic deficiency in 12 (Fanconi-Bickel's disease) and the outcome in terms of glycemia values. 4 Provide a simple diagram of how insulin affects the co-regulation of the key enzymes of glycogenesis and glycogenolysis. 5 Write a short report (maximum 1 page) addressing points 1 to 4 above. Evaluation Submit the report via Brightspace 57