4-Glycogen metabolism...pdf

Glycogen Metabolism Objectives:- After studying this topic, you should be able to:- 1. Describe the structure of glycogen and its importance as a carbohydrate reserve. 2. Describe the synthesis and breakdown of glycogen and how the processes are regulated in response to hormone action. 3...

Glycogen Metabolism Objectives:- After studying this topic, you should be able to:- 1. Describe the structure of glycogen and its importance as a carbohydrate reserve. 2. Describe the synthesis and breakdown of glycogen and how the processes are regulated in response to hormone action. 3. Describe the various types of glycogen storage diseases.  Blood glucose can be obtained from three primary sources: 1. The diet. 2. Degradation of glycogen. 3. Gluconeogensis. Glycogen :  Is a branched polymer of glucose stored mainly in the liver and muscles.  It is synthesized during the fed state from excess blood glucose.  The synthesis (glycogenesis) and degradation (glycogenolysis) take place in the cytosol.  In liver – The synthesis and breakdown of glycogen is regulated to maintain blood glucose levels.  Glycogen it is degraded to free glucose in the fasting state and released in the blood to be used by the brain and RBCs.  In muscle - The synthesis and breakdown of glycogen is regulated to meet the energy requirements of the muscle cell (exercise). Glycogen Biosynthesis (Glycogenesis) :  Occurs in the fed state  requires glycogen primer (oligosaccharide of glucose), linked to a protein known as glycogenin.  The starting intermediate is glucose 6 phosphate which is converted to glucose 1 phosphate (G1P) by the enzyme phosphoglucomutase.  G1P reacts with UTP to give UDP-Glucose by the enzyme UDP-Glucose pyrophosphorylase.  Then UDP-G acts as donor of glucose residues to the glycogen primer.  It is linked by α (1-4) glycosidic bond by the key enzyme glycogen synthase. When the main chain becomes long (more than 11 residues from the last branching point) the branching enzyme cuts the chain, taking an oligsaccharide chain of 6-7 glucose residues and link it by α(1-6) to the main chain creating a new branch.  The branching enzyme has both α(1-4) glucosidase activity and α(1-6) glucan transferase activity.  The extensive branching of glycogen increases the solubility and facilitates rapid synthesis and degradation by providing multiple sites for glycogen synthase and glycogen phosphorylase. Glycogen degradation (Glycogenolysis) :  In the liver starts in the fasting state (between meals and during sleep) and in the muscle occurs during exercise.  The key enzyme in glycogenolysis is glycogen phosphorylase.  It cleaves glucose residues from the non reducing end of glycogen molecules using inorganic phosphate (phosphorylytic cleavage).  The glucose is released as glucose 1 phosphate.  Then G1P is converted to G6P by the enzyme phosphoglucomutase.  Then, G6P is converted to free glucose by the enzyme Glucose 6 phosphatase in the liver and kidney (not in the muscle).  The glucose released from the liver glycogen can supply the brain and RBCs with energy up to 18 hours of fasting before it gets depleted.  In the muscle the G-6-phosphatase is absent , therefore G6P continues in the glycolytic pathway, for energy production.  Glycogen phosphorylase continues cleavage of glucose from the non reducing end of glycogen chain up to 4 glucose residues from the nearest branching point.  Then another enzyme called the debranching enzyme has α(1-4), α(1-6) glucosidase and α(1-4) glucan transferase activity.  It cuts the three residues-oligosaccharide from the branch by α(1-4) glucosidase and links it to the main chain by α(1-4) glucan transferase.  Then it removes the fourth glucose residue as free glucose by α(1-6) glucosidase. Control of Glycogen Metabolism :  Glycogen synthase and phosphorylase are regulated by: 1. Allosteric control 2. Hormonal regulation (covalent modification)  They are reciprocally controlled by hormones.  In the fed state we have high glucose level which stimulate insulin release from the beta cell of the pancreas.  Insulin activates glycogen synthase and inhibits glycogen phosphorylase by dephophorylating the two enzymes by activating protein phosphatase-1.  This results in glycogen synthesis.  In the fasting state glucagon is released from the alpha cell of the pancreas in response to low glucose in the blood Glucagon, in the liver activates glycogen phophorylase and inhibits glycogen synthase by phosphorylating both enzymes by Protein kinase A. Lots of breakdown of glycogen.  Muscle is insensitive to glucagon so, glycogenolysis is stimulated by norepinephrine. In the liver, activation of glycogenolysis also may occur in response to: stimulation of α1 adrenergic receptors by epinephrine and norepinephrine , vasopressin, oxytocin, and angiotensin II acting either through calcium or the phosphatidylinositol bisphosphate pathway. Glycogen storage diseases (Glycogenosis) :  Study Questions 1. What’s the importance of glucose? 2. What is the storage form in the body? Where is it stored? 3. How much glycogen can be stored? 4. What’s the significance of glycogen being highly branched? 5. Is there any difference in the functions performed by the liver and muscle glycogen? If so what is it? 6. Define glycogenesis and glycogenolysis? 7. By the aid of diagrams explain the process of glycogenesis and glycogenolysis. 8. Which hormones are involved in regulating these processes - glycogenesis and glycogenolysis? 9. How is blood glucose regulated? 10.What is glycogen storage disease and discuss one example (cause and symptoms) of such disease. Carl Ferdinand Cori Gerty Cori 5, December 1896----- 20 October 1984) 15 August, 1896 ---- 26 October, 1957 Carl Cori & Gerty Cori Catalytic conversion of glycogen Discovery of the Cori cycle Jointly won the 1947 Nobel Prize in Physiology or Medicine