Carbohydrate Metabolism V & VI

Total Page:16

File Type:pdf, Size:1020Kb

Carbohydrate Metabolism V & VI 9/13/2019 Carbohydrate Metabolism V & VI - Regulation of Glycolysis & Gluconeogenesis - - Glycogen Metabolism - FScN4621W Food Science and Nutrition University of Minnesota Unit V Regulation of Glycolysis & Gluconeogenesis 1 9/13/2019 Regulation of Glycolysis and Gluconeogenesis Regulation of Enzyme Activities Key Reactions in Glycolysis and Gluconeogenesis glycolysis Glucokinase Hexokinase Glucose glucose 6-phosphate Glucose 6-phosphatase gluconeogenesis Enzymes are regulated at both activity and gene expression levels 2 9/13/2019 Hexokinase/Glucokinase Hexokinase I ◦ Predominate in Skeletal Muscle ◦ Low Km/high affinity for glucose ◦ Activity is coordinated with GLUT4 ◦ Allosterically inhibited by its product glucose 6-phosphate ◦ Hexokinase activity controls glucose uptake and phosphorylation Hexokinase/Glucokinase Glucokinase (Hexokinase IV) ◦ Predominate in Liver and Pancreas ◦ High Km/low affinity for glucose ◦ Activity is coordinated with GLUT2 ◦ Glucokinase - GLUT2 system is very active when blood glucose is high ◦ NOT inhibited by glucose 6-phosphate ◦ Indirectly inhibited by fructose 6-phosphate (Fru-6-P) ◦ Activated by fructose 1-phosphate (Fru-1-P) ◦ Glucokinase regulatory protein is involved in the regulation by Fru-6-P and Fru-1-P 3 9/13/2019 Regulation of Glucokinase Activity Fructose Fru-1-P Fructosekinase Glucose Fru-6-P Fructose Fru -1-P GKRP nucleus + • Regulation of GK by substrates - - Fructose - Fru-1-P + - Fru-6-P - + - Glucose + + • Fructose-Fru-1-P/glucose stimulate Fru-6-P the disassociation of GK from GKRP cytosol • Fru-6-P promotes the binding of GK to GKRP, thereby inhibiting the Insulin disassociation of GK from GKRP GLUT2 • Regulation of GK by hormone Glu - Insulin + • Translocation of GK from nucleus to cytosol GK: glucokinase GKRP: glucokinase regulatory protein Liver + Stimulate or - Inhibit the disassociation of GK from GKRP Glucose 6-Phosphatase Located in Endoplasmic Reticulum (ER) Linked to glucokinase, forming a Substrate Cycle that controls glycolysis and gluconeogenesis INSULIN increases GK activity and decreases glucose 6-phosphatase activity Glucose Glucose Glucose + Pi + Fru-6-P INSULIN G6Pase INSULIN _ GK Glucose Glucose G6P G6P ER Lactate Glycogen GK GKRP N G6P: glucose-6-phosphate 4 9/13/2019 Key Reactions in Glycolysis and Gluconeogenesis glycolysis 6-Phosphofructo-1-kinase Fructose 6-phosphate Fructose 1,6-bisphosphate Fructose 1,6-biphosphatase gluconeogenesis Regulation of 6-Phosphofructo-1-kinase and Fructose 1,6-BisPhosphatase Insulin Glucagon Bifunctional enzyme 6-Phosphofructo-2-kinase/fructose 2,6-bisphosphatase Fructose 2,6-bisphosphate (F-2,6-BisP) 6-Phosphofructo-1-kinase Key enzyme in glycolysis Fructose 1,6-BisPhosphatase Key enzyme in GNG Coordinately control the rate of glycolysis and gluconeogenesis 5 9/13/2019 Fructose-2,6-Bisphosphate Fructose 2,6-bisphosphate (Fru-2,6-P2) is a metabolite, and is synthesized and broken down by the bifunctional enzyme, phosphofructokinase 2/fructose-2,6- bisphosphatase (PFK-2/FBPase-2). NOT directly involved in the glycolytic pathway F-2,6-BisP is increased by carbohydrate feeding or insulin administration glycolysis In the fasted state, when glucagon and epinephrine levels are high, F-2,6-BisP levels are low, and F-1,6-BisPase activity is increased gluconeogenesis Bifunctional Enzyme 6-Phosphofructo-2-kinase/fructose 2,6-bisphosphatase H H Fructose 6-phosphate Ser Fructose 6-phosphate ATP Pi synthesis 6PF-2kinase F2,6-Pase breakdown ADP H2O Insulin and glucagon regulate Bif via phosphorylation/dephosphorylation Fructose 2, 6-bisphosphate Fructose 2, 6-bisphosphate 6 9/13/2019 Bifunctional Enzyme 6-Phosphofructo-2-kinase/fructose 2,6-bisphosphatase Ser + + Breakdown of Synthesis of F2,6-Pase Fru 2, 6-bisphosphate 6PF-2kinase Fru 2, 6-bisphosphate Insulin and glucagon regulate Bif via phosphorylation/dephosphorylation Insulin Glucagon + - - + 6PF-2kinaseF2,6-Pase 6PF-2kinase F2,6-Pase Fructose 2,6-bisphosphate Fructose 2,6-bisphosphate (F-2,6-BisP) (F-2,6-BisP) A. Insulin Fed State glycolysis gluconeogenesis Fasted State 7 9/13/2019 Key Reactions in Glycolysis and Gluconeogenesis glycolysis Pyruvate kinase Phospoenolpyruvate pyruvate 2 1 Phosphoenolpyruvate oxaloacetate Pyruvate carboxykinase carboxylase gluconeogenesis Pyruvate Kinase (PK) Insulin Fructose 1,6-bisphosphate + Pyruvate Kinase - Glucagon Alanine 8 9/13/2019 Pyruvate Carboxylase and PEPCK Pyruvate carboxylase ◦ Positively regulated by acetyl CoA, which signals the need for more oxaloacetate PEPCK ◦ The rate determining enzyme in gluconeogenesis ◦ Activity is NOT regulated by allosteric or covalent modifiers ◦ It is changed at the gene expression level Unit VI Glycogen Metabolism ◦ Glycogenesis – glycogen biosynthesis ◦ Glycogenolysis – glycogen breakdown ◦ Regulation of glycogen metabolism 9 9/13/2019 Glycogen Glycogen – major storage carbohydrate in animals Where does it occurs? ◦ _______ and _________ The role of glycogen ◦ Liver - Release glucose to maintain blood glucose between meals or during starvation ◦ Muscle - Provide glucose for glycolysis within the muscle for muscle energy use Glycogen metabolism Glycogenesis (Glycogen synthesis) ◦ Enzymes – UDPGlc pyrophosphorylase, glycogen synthase, branching enzyme ◦ UTP (uridine diphosphate) ◦ Glycogenin Glycogenolysis (Glycogen breakdown) ◦ Enzymes - Glycogen phosphorylase, glucan transferase, debranching enzyme ◦ 10 9/13/2019 Glycogen molecule UDP-Glucose 11 9/13/2019 Formation of UDP-Glucose Glucose G-6-P G-1-P + UTP UDPGluc pyrophosphorylase UDP-Glucose Glycogenin A 37 Da protein serving as the primer molecule for glycogen synthesis First binding glucose from UDP-glucose (UDPGlc) to tyrosine residue of glycogenin Further glucose is attached to the existing glucose or glucose chain via 1-4 linkage from UDPGlc Form a short chain polysaccharide – glycogen primer with 8 glucose molecules Glycogen synthase takes over extending the chain Branching enzyme – branched chain polysaccharides 12 9/13/2019 Pathways of glycogenesis and glycogenolysis Biosynthesis Breakdown Branching Enzyme UDP Insulin Pi - - + Glycogen Glycogen cAMP Synthase Phosphorylase + - Glucagon Glucan Epinephrine Transferase UDP Debranching Enzyme UDPGlc - pyrophosphorylase UTP G-6-P Refer to Harper’s Glucokinase Glucose-6-Phosphatase Glucose Pathways of glycogenesis and Fed glycogenolysis Insulin Glucagon Biosynthesis Branching Enzyme UDP Insulin Pi - - + Glycogen Glycogen cAMP Synthase Phosphorylase + - Glucagon Glucan Epinephrine Transferase UDP Debranching Enzyme UDPGlc - pyrophosphorylase UTP G-6-P Refer to Harper’s Glucokinase Glucose-6-Phosphatase Glucose 13 9/13/2019 Pathways of glycogenesis and Fasting glycogenolysis Insulin Glucagon Breakdown Branching Enzyme UDP Insulin Pi - - + Glycogen Glycogen cAMP Synthase Phosphorylase + - Glucagon Glucan Epinephrine Transferase UDP Debranching Enzyme UDPGlc - pyrophosphorylase UTP G-6-P Refer to Harper’s Glucokinase Glucose-6-Phosphatase Glucose Regulation of glycogen metabolism cAMP-dependent regulation Hormone ◦ Insulin Insulin ◦ Glucagon (liver only) Cyclic Nucleotide ◦ Epinephrine - Phosphodiesterase Key enzyme Glycogen + + Glycogen cAMP Phosphorylase ◦ Glycogen synthase Synthase ◦ Glycogen + phosphorylase Glucagon Epinephrine Intracellular second message ◦ cAMP Which pathway does insulin or glucagon/ epinephrine promote? 14 9/13/2019 Regulation of glycogen metabolism cAMP-dependent regulation Hormone ◦ Insulin ◦ Glucagon (liver only) Insulin ◦ Epinephrine - Key enzyme Cyclic Nucleotide (catalyzes the formation of cAMP) ◦ Glycogen synthase Phosphodiesterase ◦ Glycogen AMP phosphorylase Glycogen + - Glycogen cAMP Intracellular second Synthase Phosphorylase message ◦ cAMP Which pathway does insulin or glucagon/ epinephrine promote? • High cAMP levels promote glycogen phosphorylase activity, but inhibit glycogen synthase activity • Low cAMP levels promote glycogen synthase activity, but reduce glycogen phosphorylase activity Regulation of glycogen synthase and phosphorylase activity Phosphorylation – dephosphorylation Glycogen synthase and phosphorylase exist in both phosphorylated and dephosphorylated states The effect of phosphorylation on the activity of both enzymes is opposite Glycogen synthase ◦ Glycogen synthase b - phosphorylated: INACTIVE ◦ Glycogen synthase a – dephosphorylated: ACTIVE Glycogen phosphorylase ◦ Glycogen phosphorylase a – phosphorylated: ACTIVE ◦ Glycogen phosphorylase b – dephosphorylated: INACTIVE 15 9/13/2019 Regulation of glycogen phosphorylase Phosphorylation – dephosphorylation Regulators ◦ Hormones – insulin, glucagon, epinephrine, norepinephrine ◦ cAMP concentration – effector of hormonal action ◦ cAMP-depedent protein kinase – PKA (protein kinase A) Phosphorylase b (inactive) Hormones Glucagon (liver only) cAMP PKA Epinephrine Norepinephrine P Phosphorylase a (active) Glycogen degradation Hormonal regulation of glycogen metabolism Fed state Fasted state What hormones are What hormones are secreted? secreted? Glucagon insulin ◦ ◦ Epinephrine How glycogen synthase is How glycogen synthase is regulated? regulated? ◦ increased by insulin ◦ decreased due to decreased insulin How glycogen How glycogen phosphorylase is phosphorylase is regulated? regulated? decreased due to increased insulin ◦ ◦ increased by glucagon & decreased glucagon/epinephrine & epinephrine What happens to glycogen What happens to glycogen metabolism? metabolism? ◦ glycogen stored ◦ glycogen degradation 16 9/13/2019 Regulation of glycogen phosphorylase
Recommended publications
  • • Glycolysis • Gluconeogenesis • Glycogen Synthesis
    Carbohydrate Metabolism! Wichit Suthammarak – Department of Biochemistry, Faculty of Medicine Siriraj Hospital – Aug 1st and 4th, 2014! • Glycolysis • Gluconeogenesis • Glycogen synthesis • Glycogenolysis • Pentose phosphate pathway • Metabolism of other hexoses Carbohydrate Digestion! Digestive enzymes! Polysaccharides/complex carbohydrates Salivary glands Amylase Pancreas Oligosaccharides/dextrins Dextrinase Membrane-bound Microvilli Brush border Maltose Sucrose Lactose Maltase Sucrase Lactase ‘Disaccharidase’ 2 glucose 1 glucose 1 glucose 1 fructose 1 galactose Lactose Intolerance! Cause & Pathophysiology! Normal lactose digestion Lactose intolerance Lactose Lactose Lactose Glucose Small Intestine Lactase lactase X Galactose Bacteria 1 glucose Large Fermentation 1 galactose Intestine gases, organic acid, Normal stools osmotically Lactase deficiency! active molecules • Primary lactase deficiency: อาการ! genetic defect, การสราง lactase ลด ลงเมออายมากขน, พบมากทสด! ปวดทอง, ถายเหลว, คลนไสอาเจยนภาย • Secondary lactase deficiency: หลงจากรบประทานอาหารทม lactose acquired/transient เชน small bowel เปนปรมาณมาก เชนนม! injury, gastroenteritis, inflammatory bowel disease! Absorption of Hexoses! Site: duodenum! Intestinal lumen Enterocytes Membrane Transporter! Blood SGLT1: sodium-glucose transporter Na+" Na+" •! Presents at the apical membrane ! of enterocytes! SGLT1 Glucose" Glucose" •! Co-transports Na+ and glucose/! Galactose" Galactose" galactose! GLUT2 Fructose" Fructose" GLUT5 GLUT5 •! Transports fructose from the ! intestinal lumen into enterocytes!
    [Show full text]
  • Fatty Acid Biosynthesis
    BI/CH 422/622 ANABOLISM OUTLINE: Photosynthesis Carbon Assimilation – Calvin Cycle Carbohydrate Biosynthesis in Animals Gluconeogenesis Glycogen Synthesis Pentose-Phosphate Pathway Regulation of Carbohydrate Metabolism Anaplerotic reactions Biosynthesis of Fatty Acids and Lipids Fatty Acids contrasts Diversification of fatty acids location & transport Eicosanoids Synthesis Prostaglandins and Thromboxane acetyl-CoA carboxylase Triacylglycerides fatty acid synthase ACP priming Membrane lipids 4 steps Glycerophospholipids Control of fatty acid metabolism Sphingolipids Isoprene lipids: Cholesterol ANABOLISM II: Biosynthesis of Fatty Acids & Lipids 1 ANABOLISM II: Biosynthesis of Fatty Acids & Lipids 1. Biosynthesis of fatty acids 2. Regulation of fatty acid degradation and synthesis 3. Assembly of fatty acids into triacylglycerol and phospholipids 4. Metabolism of isoprenes a. Ketone bodies and Isoprene biosynthesis b. Isoprene polymerization i. Cholesterol ii. Steroids & other molecules iii. Regulation iv. Role of cholesterol in human disease ANABOLISM II: Biosynthesis of Fatty Acids & Lipids Lipid Fat Biosynthesis Catabolism Fatty Acid Fatty Acid Degradation Synthesis Ketone body Isoprene Utilization Biosynthesis 2 Catabolism Fatty Acid Biosynthesis Anabolism • Contrast with Sugars – Lipids have have hydro-carbons not carbo-hydrates – more reduced=more energy – Long-term storage vs short-term storage – Lipids are essential for structure in ALL organisms: membrane phospholipids • Catabolism of fatty acids –produces acetyl-CoA –produces reducing
    [Show full text]
  • Glucan Phosphorylase-Catalyzed Enzymatic Reactions Using Analog Substrates to Synthesize Non-Natural Oligo- and Polysaccharides
    catalysts Review α-Glucan Phosphorylase-Catalyzed Enzymatic Reactions Using Analog Substrates to Synthesize Non-Natural Oligo- and Polysaccharides Jun-ichi Kadokawa Department of Chemistry, Biotechnology, and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima 860-0065, Japan; [email protected]; Tel.: +81-99-285-7743 Received: 9 October 2018; Accepted: 16 October 2018; Published: 19 October 2018 Abstract: As natural oligo- and polysaccharides are important biomass resources and exhibit vital biological functions, non-natural oligo- and polysaccharides with a well-defined structure can be expected to act as new functional materials with specific natures and properties. α-Glucan phosphorylase (GP) is one of the enzymes that have been used as catalysts for practical synthesis of oligo- and polysaccharides. By means of weak specificity for the recognition of substrates by GP, non-natural oligo- and polysaccharides has precisely been synthesized. GP-catalyzed enzymatic glycosylations using several analog substrates as glycosyl donors have been carried out to produce oligosaccharides having different monosaccharide residues at the non-reducing end. Glycogen, a highly branched natural polysaccharide, has been used as the polymeric glycosyl acceptor and primer for the GP-catalyzed glycosylation and polymerization to obtain glycogen-based non-natural polysaccharide materials. Under the conditions of removal of inorganic phosphate, thermostable GP-catalyzed enzymatic polymerization of analog monomers occurred to give amylose analog polysaccharides. Keywords: analog substrate; α-glucan phosphorylase; non-natural oligo- and polysaccharides 1. Introduction Oligo- and polysaccharides are widely distributed in nature and enact specific important biological functions in accordance with their chemical structures [1].
    [Show full text]
  • Defective Galactose Oxidation in a Patient with Glycogen Storage Disease and Fanconi Syndrome
    Pediatr. Res. 17: 157-161 (1983) Defective Galactose Oxidation in a Patient with Glycogen Storage Disease and Fanconi Syndrome M. BRIVET,"" N. MOATTI, A. CORRIAT, A. LEMONNIER, AND M. ODIEVRE Laboratoire Central de Biochimie du Centre Hospitalier de Bichre, 94270 Kremlin-Bicetre, France [M. B., A. C.]; Faculte des Sciences Pharmaceutiques et Biologiques de I'Universite Paris-Sud, 92290 Chatenay-Malabry, France [N. M., A. L.]; and Faculte de Midecine de I'Universiti Paris-Sud et Unite de Recherches d'Hepatologie Infantile, INSERM U 56, 94270 Kremlin-Bicetre. France [M. 0.1 Summary The patient's diet was supplemented with 25-OH-cholecalci- ferol, phosphorus, calcium, and bicarbonate. With this treatment, Carbohydrate metabolism was studied in a child with atypical the serum phosphate concentration increased, but remained be- glycogen storage disease and Fanconi syndrome. Massive gluco- tween 0.8 and 1.0 mmole/liter, whereas the plasma carbon dioxide suria, partial resistance to glucagon and abnormal responses to level returned to normal (18-22 mmole/liter). Rickets was only carbohydrate loads, mainly in the form of major impairment of partially controlled. galactose utilization were found, as reported in previous cases. Increased blood lactate to pyruvate ratios, observed in a few cases of idiopathic Fanconi syndrome, were not present. [l-14ClGalac- METHODS tose oxidation was normal in erythrocytes, but reduced in fresh All studies of the patient and of the subjects who served as minced liver tissue, despite normal activities of hepatic galactoki- controls were undertaken after obtaining parental or personal nase, uridyltransferase, and UDP-glucose 4epirnerase in hornog- consent. enates of frozen liver.
    [Show full text]
  • Carbohydrate Metabolism I & II Central Aspects of Macronutrient
    Carbohydrate Metabolism I & II - General concepts of glucose metabolism - - Glycolysis - -TCA - FScN4621W Xiaoli Chen, PhD Food Science and Nutrition University of Minnesota 1 Central Aspects of Macronutrient Metabolism Macronutrients (carbohydrate, lipid, protein) Catabolic metabolism Oxidation Metabolites (smaller molecules) Anabolic metabolism Energy (ATP) Synthesis of cellular components or energy stores Chemical Reactions Cellular Activities 2 Central Aspects of Macronutrient Metabolism High-energy compounds ◦ ATP (adenosine triphosphate) ◦ NADPH (reduced nicotinamide adenine dinucleotide phosphate) ◦ NADH (reduced nicotinamide adenine dinucleotide) ◦ FADH2 (reduced flavin adenine dinucleotide) Oxidation of macronutrients NADH NADPH FADH2 ATP and NADPH are required ATP for anabolic metabolism 3 1 Unit I General Concepts of Glucose Metabolism Metabolic pathways of glucose Glucose homeostasis Glucose transport in tissues Glucose metabolism in specific tissues 4 Overview Digestion, Absorption and Transport of Carbs ◦ Final products of digestion: ________, ________, and ________ Cellular fuels ◦ Glucose, fatty acids, ketone bodies, amino acids, other gluoconeogenic precursors (glycerol, lactate, propionate) Glucose: primary metabolic fuel in humans ◦ Provide 32% to 70% of the energy in diet of American population All tissues are able to use glucose as energy fuels ◦ Glucose has different metabolic fate in different tissues Physiological states determine glucose metabolic fate ◦ Fed/fasted – glucose is metabolized through distinct
    [Show full text]
  • Evidence for Extensive Heterotrophic Metabolism, Antioxidant Action, and Associated Regulatory Events During Winter Hardening In
    Collakova et al. BMC Plant Biology 2013, 13:72 http://www.biomedcentral.com/1471-2229/13/72 RESEARCH ARTICLE Open Access Evidence for extensive heterotrophic metabolism, antioxidant action, and associated regulatory events during winter hardening in Sitka spruce Eva Collakova1, Curtis Klumas2, Haktan Suren2,3,ElijahMyers2,LenwoodSHeath4, Jason A Holliday3 and Ruth Grene1* Abstract Background: Cold acclimation in woody perennials is a metabolically intensive process, but coincides with environmental conditions that are not conducive to the generation of energy through photosynthesis. While the negative effects of low temperatures on the photosynthetic apparatus during winter have been well studied, less is known about how this is reflected at the level of gene and metabolite expression, nor how the plant generates primary metabolites needed for adaptive processes during autumn. Results: The MapMan tool revealed enrichment of the expression of genes related to mitochondrial function, antioxidant and associated regulatory activity, while changes in metabolite levels over the time course were consistent with the gene expression patterns observed. Genes related to thylakoid function were down-regulated as expected, with the exception of plastid targeted specific antioxidant gene products such as thylakoid-bound ascorbate peroxidase, components of the reactive oxygen species scavenging cycle, and the plastid terminal oxidase. In contrast, the conventional and alternative mitochondrial electron transport chains, the tricarboxylic acid cycle, and redox-associated proteins providing reactive oxygen species scavenging generated by electron transport chains functioning at low temperatures were all active. Conclusions: A regulatory mechanism linking thylakoid-bound ascorbate peroxidase action with “chloroplast dormancy” is proposed. Most importantly, the energy and substrates required for the substantial metabolic remodeling that is a hallmark of freezing acclimation could be provided by heterotrophic metabolism.
    [Show full text]
  • Regulation of Muscle Glycogen Metabolism During Exercise: Implications for Endurance Performance and Training Adaptations
    nutrients Review Regulation of Muscle Glycogen Metabolism during Exercise: Implications for Endurance Performance and Training Adaptations Mark A. Hearris, Kelly M. Hammond, J. Marc Fell and James P. Morton * Research Institute for Sport & Exercise Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK; [email protected] (M.A.H.); [email protected] (K.M.H.); [email protected] (J.M.F.) * Correspondence: [email protected]; Tel.: +44-151-904-6233 Received: 9 January 2018; Accepted: 27 February 2018; Published: 2 March 2018 Abstract: Since the introduction of the muscle biopsy technique in the late 1960s, our understanding of the regulation of muscle glycogen storage and metabolism has advanced considerably. Muscle glycogenolysis and rates of carbohydrate (CHO) oxidation are affected by factors such as exercise intensity, duration, training status and substrate availability. Such changes to the global exercise stimulus exert regulatory effects on key enzymes and transport proteins via both hormonal control and local allosteric regulation. Given the well-documented effects of high CHO availability on promoting exercise performance, elite endurance athletes are typically advised to ensure high CHO availability before, during and after high-intensity training sessions or competition. Nonetheless, in recognition that the glycogen granule is more than a simple fuel store, it is now also accepted that glycogen is a potent regulator of the molecular cell signaling pathways that regulate the oxidative phenotype. Accordingly, the concept of deliberately training with low CHO availability has now gained increased popularity amongst athletic circles. In this review, we present an overview of the regulatory control of CHO metabolism during exercise (with a specific emphasis on muscle glycogen utilization) in order to discuss the effects of both high and low CHO availability on modulating exercise performance and training adaptations, respectively.
    [Show full text]
  • Chem331 Glycogen Metabolism
    Glycogen metabolism Glycogen review - 1,4 and 1,6 α-glycosidic links ~ every 10 sugars are branched - open helix with many non-reducing ends. Effective storage of glucose Glucose storage Liver glycogen 4.0% 72 g Muscle glycogen 0.7% 245 g Blood Glucose 0.1% 10 g Large amount of water associated with glycogen - 0.5% of total weight Glycogen stored in granules in cytosol w/proteins for synthesis, degradation and control There are very different means of control of glycogen metabolism between liver and muscle Glycogen biosynthetic and degradative cycle Two different pathways - which do not share enzymes like glycolysis and gluconeogenesis glucose -> glycogen glycogenesis - biosynthetic glycogen -> glucose 1-P glycogenolysis - breakdown Evidence for two paths - Patients lacking phosphorylase can still synthesize glycogen - hormonal regulation of both directions Glycogenolysis (glycogen breakdown)- Glycogen Phosphorylase glycogen (n) + Pi -> glucose 1-p + glycogen (n-1) • Enzyme binds and cleaves glycogen into monomers at the end of the polymer (reducing ends of glycogen) • Dimmer interacting at the N-terminus. • rate limiting - controlled step in glycogen breakdown • glycogen phosphorylase - cleavage of 1,4 α glycosidic bond by Pi NOT H2O • Energy of phosphorolysis vs. hydrolysis -low standard state free energy change -transfer potential -driven by Pi concentration -Hydrolysis would require additional step s/ cost of ATP - Think of the difference between adding a phosphate group with hydrolysis • phosphorylation locks glucose in cell (imp. for muscle) • Phosphorylase binds glycogen at storage site and the catalytic site is 4 to 5 glucose residues away from the catalytic site. • Phosphorylase removes 1 residue at a time from glycogen until 4 glucose residues away on either side of 1,6 branch point – stericaly hindered by glycogen storage site • Cleaves without releasing at storage site • general acid/base catalysts • Inorganic phosphate attacks the terminal glucose residue passing through an oxonium ion intermediate.
    [Show full text]
  • The Origins of Protein Phosphorylation
    historical perspective The origins of protein phosphorylation Philip Cohen The reversible phosphorylation of proteins is central to the regulation of most aspects of cell func- tion but, even after the first protein kinase was identified, the general significance of this discovery was slow to be appreciated. Here I review the discovery of protein phosphorylation and give a per- sonal view of the key findings that have helped to shape the field as we know it today. he days when protein phosphorylation was an abstruse backwater, best talked Tabout between consenting adults in private, are over. My colleagues no longer cringe on hearing that “phosphorylase kinase phosphorylates phosphorylase” and their eyes no longer glaze over when a “”kinase kinase kinase” is mentioned. This is because protein phosphorylation has gradu- ally become an integral part of all the sys- tems they are studying themselves. Indeed it would be difficult to find anyone today who would disagree with the statement that “the reversible phosphorylation of proteins regu- lates nearly every aspect of cell life”. Phosphorylation and dephosphorylation, catalysed by protein kinases and protein phosphatases, can modify the function of a protein in almost every conceivable way; for Carl and Gerty Cori, the 1947 Nobel Laureates. Picture: Science Photo Library. example by increasing or decreasing its bio- logical activity, by stabilizing it or marking it for destruction, by facilitating or inhibiting movement between subcellular compart- so long before its general significance liver enzyme that catalysed the phosphory- ments, or by initiating or disrupting pro- was appreciated? lation of casein3. Soon after, Fischer and tein–protein interactions.
    [Show full text]
  • Direct Interaction Between Hnrnp-M and CDC5L/PLRG1 Proteins Affects Alternative Splice Site Choice
    Direct interaction between hnRNP-M and CDC5L/PLRG1 proteins affects alternative splice site choice David Llères, Marco Denegri, Marco Biggiogera, Paul Ajuh, Angus Lamond To cite this version: David Llères, Marco Denegri, Marco Biggiogera, Paul Ajuh, Angus Lamond. Direct interaction be- tween hnRNP-M and CDC5L/PLRG1 proteins affects alternative splice site choice. EMBO Reports, EMBO Press, 2010, 11 (6), pp.445 - 451. 10.1038/embor.2010.64. hal-03027049 HAL Id: hal-03027049 https://hal.archives-ouvertes.fr/hal-03027049 Submitted on 26 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. scientificscientificreport report Direct interaction between hnRNP-M and CDC5L/ PLRG1 proteins affects alternative splice site choice David Lle`res1*, Marco Denegri1*w,MarcoBiggiogera2,PaulAjuh1z & Angus I. Lamond1+ 1Wellcome Trust Centre for Gene Regulation & Expression, College of Life Sciences, University of Dundee, Dundee, UK, and 2LaboratoriodiBiologiaCellulareandCentrodiStudioperl’IstochimicadelCNR,DipartimentodiBiologiaAnimale, Universita’ di Pavia, Pavia, Italy Heterogeneous nuclear ribonucleoprotein-M (hnRNP-M) is an and affect the fate of heterogeneous nuclear RNAs by influencing their abundant nuclear protein that binds to pre-mRNA and is a structure and/or by facilitating or hindering the interaction of their component of the spliceosome complex.
    [Show full text]
  • Glycogenosis Due to Liver and Muscle Phosphorylase Kinase Deficiency
    Pediat. Res. 15: 299-303 (198 1) genetics muscle glycogenosis phosphorylase kinase deficiency liver Glycogenosis Due to Liver and Muscle Phosphorylase Kinase Deficiency N. BASHAN. T. C. IANCU. A. LERNER. D. FRASER, R. POTASHNIK. AND S. W. MOSES'"' Pediatric Research Laborarorv. Soroka Medical Center. Iaculr~of Health Sciences. Ben-Gurion Universi!,' of Negev. Beer-Sheva, and Department of Pediatrics. Carmel Hospiral. Huifa. Israel Summary hepatomegaly. The family history disclosed that two sisters were similarly affected, whereas one older brother was apparently A four-year-old Israeli Arab boy was found to have glycogen healthy. accumulation in both liver and muscle without clinical symptoms. Past history was unremarkable. The patient's height was below Liver phosphorylase kinase (PK) activity was 20% of normal, the third percentile for his age in contrast to a normal weight. He resulting in undetectable activity of phosphorylase a. Muscle PK had a doll face and a protuberant abdomen. The liver was palpable activity was about 25% of normal, resulting in a marked decrease 9 cm below the costal margin. Slight muscular hypotonia and of phosphorylase a activity. weakness were noticeable with normal tendon reflexes. He had Two sisters showed a similar pattern, whereas one brother had slightly abnormal liver function tests. a fasting blood sugar of 72 normal PK activity. The patient's liver protein kinase activity was mg %, a normal glucagon test. and no lactic acidemia or uricemia normal. Addition of exogenous protein kinase did not affect PK but slight lipidemia. Electronmicroscopic studies of a liver biopsy activity, whereas exogenous PK restored phosphorylase activity revealed marked deposition of glycogen.
    [Show full text]
  • The Metabolic Building Blocks of a Minimal Cell Supplementary
    The metabolic building blocks of a minimal cell Mariana Reyes-Prieto, Rosario Gil, Mercè Llabrés, Pere Palmer and Andrés Moya Supplementary material. Table S1. List of enzymes and reactions modified from Gabaldon et. al. (2007). n.i.: non identified. E.C. Name Reaction Gil et. al. 2004 Glass et. al. 2006 number 2.7.1.69 phosphotransferase system glc + pep → g6p + pyr PTS MG041, 069, 429 5.3.1.9 glucose-6-phosphate isomerase g6p ↔ f6p PGI MG111 2.7.1.11 6-phosphofructokinase f6p + atp → fbp + adp PFK MG215 4.1.2.13 fructose-1,6-bisphosphate aldolase fbp ↔ gdp + dhp FBA MG023 5.3.1.1 triose-phosphate isomerase gdp ↔ dhp TPI MG431 glyceraldehyde-3-phosphate gdp + nad + p ↔ bpg + 1.2.1.12 GAP MG301 dehydrogenase nadh 2.7.2.3 phosphoglycerate kinase bpg + adp ↔ 3pg + atp PGK MG300 5.4.2.1 phosphoglycerate mutase 3pg ↔ 2pg GPM MG430 4.2.1.11 enolase 2pg ↔ pep ENO MG407 2.7.1.40 pyruvate kinase pep + adp → pyr + atp PYK MG216 1.1.1.27 lactate dehydrogenase pyr + nadh ↔ lac + nad LDH MG460 1.1.1.94 sn-glycerol-3-phosphate dehydrogenase dhp + nadh → g3p + nad GPS n.i. 2.3.1.15 sn-glycerol-3-phosphate acyltransferase g3p + pal → mag PLSb n.i. 2.3.1.51 1-acyl-sn-glycerol-3-phosphate mag + pal → dag PLSc MG212 acyltransferase 2.7.7.41 phosphatidate cytidyltransferase dag + ctp → cdp-dag + pp CDS MG437 cdp-dag + ser → pser + 2.7.8.8 phosphatidylserine synthase PSS n.i. cmp 4.1.1.65 phosphatidylserine decarboxylase pser → peta PSD n.i.
    [Show full text]