1. Glycogen Metabolism Dr. Samah Kotb 2015 Cellular Biochemistry and Metabolism2 (CLS 333)

2. GLYCOGEN METABOLISM CHAPTER 5

3. Introduction

4. Glycogen

5. Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals and fungi. The polysaccharide structure represents the main storage form of glucose in the body.

6. In humans, glycogen is made and stored primarily in the cells of the liver and the muscles, and works as the secondary long-term energy storage (with the primary energy stores being fats held in adipose tissue).

7. Muscle glycogen is converted into glucose by muscle cells, and liver glycogen converts to glucose for use throughout the body including the central nervous system.

8. Glycogen is the analogue of starch, a glucose polymer and energy storage in plants, having a similar structure to amylopectin (a component of starch), but more extensively branched and compact than starch.

9. Glycogen is found in the form of granules in the cytosol /cytoplasm in many cell types, and plays an important role in the glucose cycle.

10. Glycogen forms an energy reserve that can be quickly mobilized to meet a sudden need for glucose, but one that is less compact than the energy reserves of triglycerides (lipids).

11. In the liver cells (hepatocytes), glycogen can compose up to 8% of its fresh weight (100 –120 g in an adult) soon after a meal.

12. Only the glycogen stored in the liver can be made accessible to other organs. In the muscles, glycogen is found in a low concentration (1-2% of the muscle mass).

13. The amount of glycogen stored in the body especially within the muscles, liver, and red blood cells mostly depends on physical training, basal metabolic rate, and eating habits such as intermittent fasting.

14. Small amounts of glycogen are found in the kidneys, and even smaller amounts in certain glial cells in the brain and white blood cells. The uterus also stores glycogen during pregnancy to nourish the embryo.

15. Glucose is a simple sugar. It is a form of carbohydrate. It is the main source of energy for our bodies. Glycogen is the storage form of glucose in our bodies.

16. Tissue glycogen is an important energy reservoir, its breakdown is carefully controlled. Glycogen consists of high molecular weight granules. Glycogen

17. Liver Cell Glycogen in liver cell

18. In liver – The synthesis and breakdown of glycogen is regulated to maintain blood glucose levels. In muscle - The synthesis and breakdown of glycogen is regulated to meet the energy requirements of the muscle cell. Glycogen function

19. Degradation: glycogen n + P i → Glycogen n-1 + glucose 1-phosphate. Synthesis: Glycogen n + UDP-glucose → Glycogen n+1 + UDP. Glycogen is synthesized via uridine diphosphate glucose (UDP – glucose). Glycogen synthesis and degradation utilize separate pathways. Glycogen metabolism

21. Glycogenolysis is a catabolic process; the breakdown of glycogen to glucose units. Glycogen is principally stored in the cytosol granules of :- – Liver – Muscle Glycogenolysis

22. Glucose 6- phosphate has 3 fates.

23. Glucose from storage (or diet). α-Amylase is an endoglycosidase, It cleaves amylopectin or glycogen to maltose, maltotriose and other small oligosaccharides. It is active on either side of a branch point, but activity is reduced near the branch points. Debranching enzyme cleaves limit dextrins. Glycogenolysis

25. Glycogen phosphorylase catalyzes the breakdown of glycogen. Glycogen + Pi  Glucose 1- phosphate + glycogen ( n residues ) (n-1 residues)

26. Glycogen phosphorylase uses pyridoxal phosphate (PLP) a derivative of pyridixine (vitamine B 6 ) as a coenzyme. B 6 is required for the mobilization of glucose from glycogen. It is also required for other biochemical reactions such as transamination.

27. Phosphorylase is specific for the α-1,4 linkage. Two additional enzymes are required

28. Glycogen phosphorylase cleaves glucose from the nonreducing ends of glycogen molecules. This is a phosphorolysis, not a hydrolysis. Metabolic advantage: product is a sugar phosphate. The glucose- 1-phosphate is converted to glucose 6-phosphate by phosphoglucomutase. Glycogenolysis

31. Glucose units are activated for transfer by formation of sugar nucleotides. Other example of activation is acetyl-CoA (acetate). Leloir showed in the 1950s that glycogen synthesis depends on sugar nucleotides by UDP-glucose pyrophosphorylase. Glycogen synthesis

32. Luis Leloir Nobel Prize in Chemistry, 1970 “ for his discovery of sugar nucleotides and their role in the biosynthesis of carbohydrates”

33. UDP glucose is the activated form of glucose. Acetyl CoA is the activated form of acetate.

34. Glycogen Synthesis pathway

35. UDP-glucose pyrophosphorylase Glucose 1-phosphate + UTP  UDP-glucose + PP i. pp i + H 2 O → 2P i. Glucose 1-phosphate + UTP + H 2 O → UDP-glucose + 2P i. Although the reaction is reversible the hydrolysis of the pyrophosphate pushes it to the right.

36. forms α-(1→4) glycosidic bonds in glycogen. Glycogenin (a protein) forms the core of a glycogen particle. Glycogen synthase transfers glycosyl units (glucose) from UDP-glucose to C-4 hydroxyl, at a non reducing end of a glycogen strand. Glycogen synthase

37. Glucose is added to the non-reducing end. UDP Glycogen synthase catalyzes α-1,4 linkages

38. Glycogen synthesis Glucose 6-P→ glucose 1-P. glucose 1-P + UTP→UDP-glucose + PP i. PP i + H 2 O→ 2 P i. UDP-glucose + glycogen n → glycogen n+1 + UDP. UDP + ATP → UTP + ADP. Glucose 6-P + ATP + glycogen n + H 2 O → glycogen n+1 + ADP + 2P i. Only one ATP is used to store one glucose residue in glycogen.

39. Regulation of Glycogen metabolism

40. Highly regulated process involving reciprocal control of glycogen. Glycogen phosphorylase and glycogen synthase are regulatory enzymes in glycogenolysis and glycogen synthesis. Regulation of Glycogen metabolism

41. Glycogen phosphorylase in glycogenolysis allosterically :- 1)Activated by AMP. 2)Inhibited by ATP and glucose-6-P. Glycogen synthase in glycogen synthesis is stimulated by glucose-6-P. Both enzymes are regulated by covalent modification phosphorylation. Regulation of Glycogen metabolism

42. When the enzyme is phosphorylated, it is inactivated.  Active “a” form to inactive phosphorylated “b” form. Notice that phosphorylation has the opposite effect on glycogen phosphorylase; phosphorylation activates.  Glycogen synthase is the regulatory enzyme in the synthesis of glycogen.  The enzyme is regulated by covalent modification and phosphorylation. Regulation of Glycogen metabolism

43. Hormonal Regulation of Glycogen metabolism

44. Examples :- Glucagon and epinephrine. Glucagon and epinephrine stimulate glycogen breakdown - opposite effect of insulin. Glucagon is also secreted by pancreas. Hormonal Regulation

45. Liver is responsive to glucagon Glucagon signal, a cascade of molecular events leading to glycogen breakdown. It utilizes a G-protein-dependent signal- transduction pathway. Glucagon stimulate glycogen breakdown

46. A few hormone molecules cause the release of large amounts of glucose, a cascade. Glucagon

47. Glucagon acts in liver and adipose tissue only. Epinephrine (adrenaline) is released from adrenal glands. Epinephrine acts on liver and muscles. The phosphorylase cascade amplifies the signal. Hormonal Regulation

48. The difference between epinephrine and glucagon: Both are glycogenolytic but for different reasons:- 1) Epinephrine is the fight or flight hormone, rapidly mobilizes large amounts of energy. 2) Glucagon is for long-term maintenance of steady- state levels of glucose in the blood. 3) activates glycogen breakdown. 4) activates liver gluconeogenesis.

49. Glycogen synthesis and breakdown are reciprocally regulated Red=inactive forms, green = active forms. Protein phosphatase 1 (PP1) regulates glycogen metabolism. Inactive Active

50. PP1 dephosphorylates phosphorylase kinase and phosphorylase a, thus inactivating glycogenolysis. PP1 also dephosphorylates glycogen synthase b, thus activating glycogen synthesis. Protein phosphatase 1

51. PP1 dephosphorylates phosphorylase kinase and phosphorylase a thus inactivating glycogenolysis.

52. PP1 dephosphorylates glycogen synthase b thus activating glycogen synthesis

53. When blood glucose levels are high, insulin activates protein phosphatase 1 which stimulates glycogen synthesis. – This is accomplished through a complex highly regulated signal transduction pathway. Remember: Glycogen metabolism in liver regulates blood glucose levels.

54. Blood glucose levels rise after ingestion of carbohydrates, leading to glycogen synthesis. Inactivation of phosphorylase and an activation of glycogen synthase. Liver

55. Glucogon = starved state; stimulates glycogen breakdown, inhibits glycogen synthesis. High blood glucose levels = fed state; insulin stimulates glycogen synthesis and inhibits glycogen breakdown.

56. Insulin is a Peptide Hormone Note that the portal vein is the only vein in the body that feeds an organ. Note the other effects of insulin Glycogen synthesis Insulin is secreted from the pancreas (to liver) in response to an increase in blood glucose. Insulin stimulates glycogen synthesis and inhibits glycogen breakdown