Glycogen metabolism and its regulation

Slides include Glycogenesis and Glycogenolysis along with regulation and Glycogen Storage Disease

1. 1 By: A kanksha Dubey Assistant Professor People’s College of Medical Sciences and Hospital Bhopal

2. Glycogen was discovered by Claude Bernard (he discovered that liver can generate reducing sugar) Carl and Gerty Cori were awarded Nobel prize in 1947, for their work on glycogen degradation. Glycogen is a Multi branched polysaccharides of glucose that serves as a energy storage form in human, animals, bacteria and plants(which are devoid of chlorophyll system s/a yeast, fungi) 2

3. It is main storage form of glucose in the body and readily mobilized also hence c/a Animal starch It is Dextrorotatory, formation is k/a Glycogenesis and Degradation is k/a Glycogenolysis Most of the glucose residues in glycogen are linked by α-1,4-glycosidic bonds and Branches residue are created by α-1,6-glycosidic bonds. It is a polymer of D Glucose units hence resemble amylopectin 3

4. Glycogen and TG serve as long term energy reserve of the body.

5. Glycogen is a polymer of glucose residues linked by a (1  4) glycosidic bonds, mainly a (1  6) glycosidic bonds, at branch points .

6. Glycogen is present in the cytosol in the form of granules ranging in diameter from 10 to 40 nm .

7. Why branching ? The highly branched structure of glycogen provides a large number of sites (terminal residues- non reducing ends)for synthesis and degradation of glycogen, permitting rapid storage of extra glucose after meals or release of glucose 1-phosphate for muscle activity.

8. Functions of Glycogen Glycogen is the storage form of carbohydrates in the human body. The major sites of storage are liver and muscle . When blood glucose level falls, liver glycogen is largely concerned with storage and supply of Glucose-1-phosphate which is converted to Glucose for maintenance of blood glucose level between the meals.

9. 3. Muscle glycogen is responsible for providing energy to muscle itself through Glycolysis. Muscle glycogen can’t contribute to blood glucose level. The function of muscle glycogen is to act as reserve fuel for muscle contraction. 4. All the enzymes related to glycogen metabolism are cytoplasmic .

10. It is stored mainly in liver and muscle The liver content of glycogen is greater than that of muscle, Since the muscle mass of the body is considerably greater than that of the liver, about three-quarters of total body glycogen is in muscle

11. Percentage of Tissue Weight Tissue Weight Body Content Liver glycogen 4-6 % 1.8 kg 72-108 g m Muscle g l y co g en 0.7 -1 % 35 kg 245 -350 g m Ext r ac e l l ular glucose 0.1 % 10 L 10 g m

12. Why Glycogen is Used as Reserve form of energy Glycogen serves as a buffer to maintain blood-glucose levels. Glucose is the only fuel used by the brain, except during prolonged starvation. The glucose from glycogen is readily mobilized and is therefore a good source of energy for sudden, strenuous activity .

13. Being insoluble it exerts no Osmotic Pressure and so do not disturb the intracellular fluid content (same amount of glucose will triple the osmotic pressure and cells will burst) Glucose can provide energy in anaerobic condition also. Fatty acids can not cross blood barrier hence glucose is only source of energy to brain

14. Glycogen Metabolism Glycogenesis Glycogenolysis

15. Glycogenesis is the synthesis of glycogen from glucose. Glycogenesis mainly occurs in Muscle a nd Liver. Muscle glycogen provides a readily available source of glucose for glycolysis within the muscle itself. Liver glycogen functions to store and export glucose to maintain blood glucose between meals /Fasting state

16. Steps of Glycogenesis Polymerization of glucose into Glycogen is k/a Glycogenesis. Thermodynamically it is Endergonic reaction which require ATP and UTP The following enzyme reactions occur in glycogen synthesis: 1. Synthesis of an Activated Precursor , UDP-glucose, by UTP: Glucose-1-phosphate Uridyltransferase 2. Initiation of Glycogen Synthesis by Glycogenin 3. Introduction of branches by Branching Enzyme 4. Chain elongation by Glycogen Synthase 5. Repetition steps 3 and 4

17. Hexokinase in Muscle Glucokinase in liver , Magnesium is required is required in both the steps PPi formed is converted to inorganic phosphatase(pi) by Pyrophosphatase enzyme , which makes reaction Irreversible 1 UTP is utilized here UDP Glucose is active form of Glucose, C1 of UDP-G forms glycosidic bond with C4 of glycogenin to form Glycogen Primer

18. Glycogen primer receives 7-8 glucose units on its own this reaction is catalyzed by glycogenin itself and after that reaction is catalyzed by Glycogen synthase(Key enzyme) Glycogen Synthase which adds glucose units to primer upto 11 units. UDP is converted to UTP by Nucleoside Diphosphate Kinase which is further reutilized in reaction After 11 glucose units Branching enzyme is introduced which transfer 6 glucose units to branching point.(alpha 1,4 to alpha 1,6) Chain elongation by Glycogen Synthase and Branching by branching enzyme is repeated

19. Glycogenin initiates glycogen synthesis. It is primer for new chain synthesis and enzyme too that catalyze its synthesis. Glycogenin is an enzyme that catalyzes attachment of a glucose molecule to one of its own tyrosine residues. It is homodimer of 37 KDa which adds up only 7-8 residues of glucose after that chain is elongated by Glycogen synthase

20. The overall reaction of the glycogen synthesis for the addition of each glucose residue is (Glucose)n + Glucose + 2ATP ------> (Glucose)n*1 +2ADP+Pi Of the Two ATP utilized , one is required for the phosphorylation of glucose while the other is needed for conversion of UDP to UTP.

21. Purpose of Glycogenolysis The controlled breakdown of glycogen and release of glucose increase the amount of glucose between meals. Hence, glycogen serves as a buffer to maintain blood-glucose levels. Glycogen's role in maintaining blood glucose levels is especially important because glucose is virtually the only fuel used by the brain, except during prolonged starvation.

22. The glucose from glycogen is readily mobilized and is therefore a good source of energy for sudden, strenuous activity. Unlike fatty acids, the released glucose can provide energy in the absence of oxygen and can thus supply energy for anaerobic activity.

23. GLYCOGENOLYSIS The degradation of stored glycogen in liver and muscle constitutes Glycogenolysis. The pathways for the synthesis and degradation of glycogen are not reversible. An independent set of enzymes present in the cytosol carry out Glycogenolysis. Glycogen is degraded by breaking α 1 ,4- and α 1,6-Glycosidic bonds

24. The alpha 1,4-glycosidic bonds (from the non-reducing ends) are cleaved sequentially by the enzyme Glycogen Phosphorylase to yield glucose 1-phosphate. This process-called phosphorolysis and this continues until four glucose residues remain on either side of branching point (a-1,6glycosidic linkage). The glycogen so formed is known as limit dextrin which cannot be further degraded by Phosphorylase. The branches of glycogen are cleaved by two enzyme activities present on a single polypeptide called Debranching Enzyme , hence it is a Bifunctional Enzyme . Alpha 1,4 transferase activity removes a fragment of three or four glucose residues attached at a branch and transfers them to another chain.

25. Alpha 1,6 Glucosidase breaks the alpha1,6 bond at the branch with a single glucose residue and releases a free glucose. The remaining molecule of glycogen is again available for the action of Phosphorylase and debranching enzyme to repeat the reactions stated in 1 and 2. Through the combined action of glycogen Phosphorylase and debranching enzyme glucose 1-phosphate and free glucose in a ratio of 8 : 1 are produced. Glucose 1 -phosphate is converted to glucose 6-phosphate by the enzyme phosphoglucomutase The fate of glucose 6-phosphate depends on the tissue. The liver, kidney and intestine contain the enzyme glucose 6-phosphatase that cleaves glucose 6-phosphate to glucose. This enzyme is absent in muscle and brain, hence free glucose cannot be produced from glucose 6-phosphate in these tissues. In the peripheral tissues, glucose 6-phosphate produced by Glycogenolysis will be used for glycolysis

26. MULTIPLE FATES OF GLUCOSE-6-PHOSPHATE

27. Lysosomal glycogen disposal A small amount (1–3%) of glycogen is continuously degraded by the lysosomal enzyme, α ( 1 → 4 ) -Glucosidase ( acid maltase ) . The purpose of this pathway is unknown. In liver cells, approximately 10% of all glycogen particles are found inside Lysosomes , where they undergo slow degradation by acid maltase.

28. However, a deficiency of this enzyme causes accumulation of glycogen in vacuoles in the Lysosomes, resulting in the serious glycogen storage disease Type II: Pompe's disease Type II: Pompe's disease is the only glycogen storage disease that is a lysosomal storage disease

29. Regulation of Glycogenesis and Glycogenolysis A good coordination and regulation of glycogen synthesis and its degradation are essential to maintain the blood glucose levels. Glycogenesis and Glycogenolysis are, respectively, controlled by the enzymes glycogen synthase and glycogen Phosphorylase. Regulation of these enzymes is accomplished by three mechanisms

30. Allosteric regulation Hormonal regulation Influence of calcium

31. Allosteric regulation of glycogen metabolism There are certain metabolites that allosterically regulate the activities of Glycogen Synthase and Glycogen Phosphorylase. The control is in such a way that glycogen synthesis is increased when substrate is available and energy levels are high(ATP) and Glycogenolysis is enhanced when glucose concentration and energy levels are low.

32. In a well-fed state, the availability of glucose-6-phosphate is high which allosterically activates glycogen synthase for more glycogen synthesis. On the other hand, glucose 6-phosphate and ATP allosterically inhibit glycogen Phosphorylase. Free glucose in liver also acts as an Allosteric inhibitor of glycogen Phosphorylase.

33. Hormonal regulation of glycogen metabolism The hormones, through a complex series of reactions, bring about covalent modification, namely Phosphorylation and Dephosphorylation of enzyme proteins which, ultimately control glycogen synthesis or its degradation

34. Regulation of glycogen synthesis by cAMP The Glycogenesis is regulated by glycogen synthase. This enzyme exists in two forms Glycogen Synthase ‘a’: Dephosphorylated (Active) glycogen synthase 'b’: Phosphorylated (Inactive) Glycogen synthase 'a‘ (active) can be converted to 'b' form (inactive) by phosphorylation.

35. Glycogen degradation is not just the reverse of glycogenesis Glycogenesis Formation of activated precursor UDP Glucose Initiation by Glycogenin Branching by branching enzyme Elongation by Glycogen Synthase Repetition of above 3 and 4 steps Glycogenolysis Depolymerization of linear strands by Phosphorylase Debranching enzyme activity Repetition of above steps Conversion of Glucose-1-P to Glucose-6-P Conversion of Glucose-6-P to free Glucose

36. These are a group of genetic diseases that result from a defect in an enzyme required for glycogen synthesis or degradation. They result either in formation of glycogen that has an abnormal structure, or in the accumulation of excessive amounts of normal glycogen in specific tissues as a result of impaired degradation. 8/12/2012 56

37. A particular enzyme may be defective in a single tissue, such as liver (resulting in hypoglycaemia) or muscle (muscle weakness), or the defect may be more generalized, affecting liver, muscle, kidney, intestine, and myocardium. The severity of the glycogen storage diseases (GSDs) ranges from fatal in infancy to mild disorders that are not life-threatening.

38. Glycogen Storage Disease Type-I It is also called Von Gierke's Disease. Most common type of glycogen storage disease is type I. Incidence is 1 in 100,000 live births. Patients with Type І GSD are unable to release glucose from glycogen due to the deficiency of Glucose-6- Phosphatase and hence with time glycogen builds up in the liver.

39. Characterized by massive enlargement of liver (hepatomegaly), growth retardation, fasting hypoglycemia, increased lactic acid concentrations in the blood (due to excessive glycolysis),

40. Hyperuricemia( Glucose-6-phosphate is accumulated, so it is channelled to HMP shunt pathway producing more ribose and more nucleotides. Purines are then catabolised to uric acid, leading to hyperuricemia

41. Type І b has been identified as a defect in the glucose–6–phosphatase transport system . Very rare

42. Type II Called as Pompe disease Deficiency of Lysosomal α-1,4 and α 1,6 glucosidase (Acid Maltase) Primary organ involved: all organs with Lysosomes A homozygous deficiency of acid maltase disrupts lysosomal glycogen degradation and results in glycogen accumulation. Skeletal and heart muscle are more strongly affected than the liver. Glycogen accumulation interferes with muscle cell function and contraction, and heart failure leads to death.

43. The condition, can vary in severity; complete lack of enzyme activity becomes manifest in infants, whereas mutations that reduce but do not completely inactivate the enzyme will cause milder disease with onset deferred to later childhood or adolescence. The disease can be treated with enzyme replacement therapy.

44. Type III Limit Dextrinosis/ Forbes's / Cori’s Disease Primary Organ involved: liver, skeletal muscle and heart Deficiency of Amylo-1, 6–Glucosidase (Debranching enzyme) results in storage of an abnormal form of glycogen. Accumulation of abnormal glycogen having short chain glycogen, hypoglycemia

45. Type IV Anderson’s Disease / Amylopectinosis Absence of Branching Enzyme (Amylo 1,4 to 1,6 transglucosidase) Primary Organ involve: liver These patients experience muscle pain, cramps, fatigue and muscle tenderness. accumulation of abnormal glycogen, having few branches, early death due to liver and cardiac failure

46. Type V McArdle Disease Absence of Muscle Glycogen Phosphorylase Primary Organ involve: Skeletal Muscle(glucose cannot be released from the glycogen stored in skeletal muscles for energy) These patients experience muscle pain, cramps, fatigue and muscle tenderness. With the breakdown of muscle and the release of myoglobin , myoglobinuria may develop.

47. Type VI Type VI GSD also known as Hers’ disease is a rare disorder due to the deficiency of Liver Phosphorylase Primary organ involved is liver Enlargement of liver due to increased deposit of glycogen, ketosis and mild hypoglycemia are seen.

48. Type VII Tarui’s Disease Deficiency of Phosphofructokinase in RBC and Muscle Primary organ involved : Muscle and RBC Patients have deposition of abnormal glycogen in muscle. Muscular pain, cramps, decrease serum lactate after exercise, and hemolytic anaemia

49. Glycogen represents the principal storage form of carbohydrate in the body, mainly in the liver and muscle. Glycogen is synthesized from glucose by the pathway of glycogenesis. It is broken down by a separate pathway, glycogenolysis. Glycogenolysis leads to glucose formation in liver and lactate formation in muscle owing to the respective presence or absence of glucose 6-phosphatase . 60

50. Cyclic AMP integrates the regulation of glycogenolysis and Glycogenesis by promoting the simultaneous activation of Phosphorylase and inhibition of glycogen synthase. Insulin acts reciprocally by inhibiting Glycogenolysis and stimulating Glycogenesis. Inherited deficiencies in specific enzymes of glycogen metabolism in both liver and muscle are the causes of glycogen storage diseases.