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Glycogen Metabolism
- 2. Outline: General view & biomedical importance Synthesis of glycogen Degradation of glycogen Regulation.
- 3. Glycogen- bank account. “a friend in need is a friend indeed” Glucose- essential for energy Glycogen - stored - when glucose is abundant - degraded - when glucose is below normal glycogen glucose
- 4. Claude Bernard, 1857, isolated glycogen Carl Cori & Gerty Cori, NP, 1947, glycogen degradation Luis Leloir, Argentina, NP, 1970, glycogen synthesis Earl Sutherland, NP 1971, role of cAMP General overview • Polymer of α-D glucose, 108 Da • Liver and muscle, liver content more than muscle • Muscle has more glycogen than liver. • Muscle- synthesis of ATP, Liver- blood glucose %age of weight Tissue weight Body content Liver glycogen 5.0 1.8 90 gm. Muscle glycogen 0.7 35 245 gm. Extracellular glucose 0.1 10 L 10 gm.
- 5. General view & biomedical importance • Liver glycogen after a fast of 12-18 hours falls by 125% • Muscle pyruvate transamination Gluconeogenesis liver muscle • 8% muscle glycogen release glucose • Exercise triggers mobilization to form ATP
- 6. In muscles- Red muscle White muscle Rich blood flow Poor blood supply Large no of mitochondria & Oxygen Lesser Pyruvate Lactate End product- CO2 & H2O Substrate for glycolysis Can work for longer period Short period
- 7. Glycogen • Composed entirely of glucosyl residues • Linked together by α- 1, 4 glycosidic linkages • 8-10: branch, α- 1, 6 linkage • Branch- large sites for glycogenolysis: glucose 1-(P) • Stored as granules: cytoplasm • Formation of branch: slower • Liver glycogen store increase in well fed state • Depleted during fast • Muscle glycogen not affected by fasting
- 8. I. Synthesis of glycogen: A. Synthesis of UDP-glucose Glucose-6-℗ Glucose-1-℗ phosphoglucomutase UTP PPi UDP- glucoseUDP- glucosepyropho sphorylase 2 Pi H20 Pyrophosphatase hydrolysis
- 9. Inter-conversion of glucose-6- phosphate to glucose-1-phosphate Glucose- 1,6 bisphosphate Glucose-1-℗ phosphoglucomutase phosphoglucomutase
- 10. B. Synthesis of a primer to initiate glycogen synthesis UDP - UDP Glycogen synthase Tyr-OH Tyr-O- Tyr-O- Glycogen synthase Glycogenin primer
- 11. • Protein • An enzyme • 37 kDa • Constitutes of 332 amino acids • Glycosylation occurs at tyrosine residue • The –OH group of Tyr serves as the site • Reaction catalyzed by Glycogenin itself
- 12. Tyr-O- α- 1, 4 glycosidic linkages C. Elongation of chain by glycogen synthase Non-reducing end Glycogen synthase O O O CH2OH CH2OH UDP + ATP UTP + ADP Nucleoside diphosphate kinase
- 13. Summary Glucose-6-℗ Glucose-1-℗ phosphoglucomutase UTP PPi UDP- glucoseUDP- glucosepyrophosphor ylase 2 Pi H20 hydrolysis UDP Glycogen synthase Tyr-OH Tyr-O- Tyr-O- Glycogen synthase
- 14. D. Formation of branches Tyr-O- Action of enzyme α- (1, 4), α- (1, 6) transglucosidase α- 1, 6 glycosidic linkage 4:6 transferase Non-reducing ends
- 15. E. Synthesis of additional branches • After elongation of the two ends • The new formed 6- 8 glucosyl residues are removed • Added & the additional branches made • α- (1, 4), α- (1, 6) transglucosidase and 4:6 transferase are together called the “branching enzyme” O O CH2OH CH2OH O α- (1, 6) glycosidic linkage
- 16. ll. Degradation of Glycogen • Not a reversal of synthetic pathway • A separate set of cytosolic enzyme is required • Primary product is • Glucose-1- phosphate • Glucose
- 17. A. Shortening of chains: Tyr-O- Glycogen phosphorylase6 Pi PLP
- 18. B. Removal of branches: Tyr-O- Oligo α- (1, 4), α- (1, 4) glucantransferase Formation of α- (1, 4) linkage by 4:4 transferase Action of amylo α- (1, 6) glucosidase H20 Tyr-O- Glucose-1-℗ Glycogen phosphorylase
- 19. C. Fate of glucose-1- phosphate in liver and muscled Glucose-6-℗glucose H2O Pi Glucose-6- phosphatase Released into blood to maintain blood glucose level Glycolysis Energy for muscle contraction
- 20. D. Lysosomal degradation of glycogen • Small amount: glycogen, 1-3% degraded continuously • Purpose: unknown • The enzyme: alpha (1, 4) glucosidase, alias acid maltase • Deficiency: accumulation of glycogen • Pompe’s disease type II: only lysososmal storage disease
- 21. SPECIAL FEATURES OF GLYCOGEN DEGRADATION AND SYNTHESIS • WHY STORE GLUCOSE AS GLYCOGEN? • WHY NOT JUST PUMP GLUCOSE INTO CELLS? • WHY GLYCOGEN IS A BRANCHED MOLECULE WITH ONLY ONE BEGINNING AND MANY BRANCHES TERMINATING WITH NON REDUCING GLUCOSYL END? • WHY IS PRIMER NEEDED FOR GLYCOGEN SYNTHESIS? • WHY DOES GLYCOGEN LIMIT ITS OWN SYNTHESIS?
- 22. WHY STORE GLUCOSE AS GLYCOGEN? • Why not store it as fat? • Why waste so many ATP to synthesize glycogen? – The answer is • Fat stored, not mobilized rapidly as glycogen. • Cannot be used as source of energy: absent O2 • Fat: cannot be converted to glucose to maintain its level
- 23. WHY NOT JUST PUMP GLUCOSE INTO CELLS? • Glucose: osmotically active • Costs ATP to pump glucose • Concn. of 400 mM to match the “glucose reserve” • Balanced by outward movement • Uptake of water: lysis • High MW; 400 mM glucose stored; intracellular glycogen; concentration of 0.01 mM • No osmotic pressure problem
- 24. WHY GLYCOGEN IS A BRANCHED MOLECULE WITH ONLY ONE BEGINNING AND MANY BRANCHES TERMINATING WITH NON REDUCING GLUCOSYL END? • Numerous sites: glycogen phosphorylase & glycogen synthase • α amylose: polymer: only one non reducing end • Slower • glycogen phosphorylase & glycogen synthase: tight association with glycogen • Ready access to multitude of non- reducing sugars
- 25. WHY IS PRIMER NEEDED FOR GLYCOGEN SYNTHESIS? • glycogen synthase: low Km- large glycogen Km glycogen • Glucose alone: can’t act as primer • Glycogen: immortal • Glycogenin: a primer • Alas! Glycogen: mortal
- 26. WHY DOES GLYCOGEN LIMIT ITS OWN SYNTHESIS? • glycogen synthase efficient with larger glycogen • How does glycogenesis stop? • glycogen synthase ‘a’: decreases with accumulation of glycogen • Glycogen inhibits the dephosphorylation of glycogen synthase ‘b’ by phosphoprotein phosphatase
- 27. III. REGULATION OF GLYCOGEGESIS & GLYCOGENOLYSIS • LIVER: glycogenolysis accelerates in fasting • MUSCLE: glycogenolysis in active exercise Glycogenesis when muscle is at rest • 2 levels: – Hormonal regulation – Allosterically controlled
- 28. A. Activation of glycogen degradation by cAMP mediated pathway I. Activation of protein kinase A glucagon epinephrine GPCR ATP cAMP Active Adenyl cyclase PKA ‘b’ PKA ‘a’ Inactive enzymes Active enzyme
- 29. II. Activation of phosphorylase kinase cAMP dependent PKA ‘a’ Glycogen phosphorylase kinase ‘b’ Glycogen phosphoryla se kinase ‘a’ATP ADP H2O Pi Protein phosphatase-1INSULIN
- 30. INSULIN SIGNAL CASCADE Insulin receptor tyrosine kinase ‘b’ Insulin receptor tyrosine kinase ‘a’ Insulin receptor substrate ‘b’ (IRS-Tyr) Insulin receptor substrate ‘a’ (IRS-Tyr) Protein phosphatase ‘b’ Protein phosphatase ‘a’ Biological effect
- 31. III. Activation of glycogen phosphorylase Glycogen phosphorylase kinase ’a’ Glycogen phosphorylase ‘b’ Glycogen phosphorylase ‘a’ATP ADP H2O Pi Protein phosphatase-1INSULIN GLYCOGENOLYSIS
- 32. Summary glucagon epinephrine GPCR ATP cAMP Active Adenyl cyclase PKA ‘b’ PKA ‘a’ Glycogen phosphorylase kinase ‘b’ Glycogen phosphorylase kinase ‘a’ ATP ADP H2O Pi Protein phosphatase-1 INSULIN Glycogen phosphorylase ‘b’ Glycogen phosphorylase ‘a’ ATP ADP H2O Pi Protein phosphatase-1 GLYCOGENOLYSIS
- 33. B. Inhibition of glycogen synthesis by cAMP directed pathway glucagon epinephrine GPCR ATP cAMP Active Adenyl cyclase PKA ‘b’ PKA ‘a’ Glycogen synthase ‘a’ Glycogen synthase ‘b’ ATP ADP H2O Pi Protein phosphatase-1 INSULIN INHIBITION OF GLYCOGEN SYNTHESIS
- 34. C. Allosteric regulation of glycogen synthesis and degradation • Glycogen synthase & glycogen phosphorylase respond to the energy needs of the cell • Glycogenesis: glucose is high • Glycogenolysis: glucose; energy level low • Allosteric regulation: rapid response • Can override the effects of hormone mediated regulation
- 35. I. Regulation of glycogen synthesis and degradation in well-fed state GLYCOGEN GLUCOSE-1-℗ Glycogen synthase Glycogen phosphorylase GLYCOGEN GLUCOSE-1-℗ Glycogen synthase Glycogen phosphoryl ase GLUCOSE GLUCOSE-6-℗ ATP AMP
- 36. II. Activation of glycogen degradation by calcium a. Calcium activation of muscle phosphorylase kinase Nerve impulse Membrane depolarisation Ca Ca Ca Ca Calmodulin Ca CaCa Ca Muscle phosphorylase ‘b’ Muscle phosphorylase ‘a’ Glycogen phosphorylase ‘b’ Glycogen phosphorylase ‘a’ Pi H20 GLYCOGENOLYSIS
- 37. b. Calcium activation of liver phosphorylase kinase ER Membrane depolarisationCa Ca Ca Ca Calmodulin Ca CaCa Ca Liver phosphorylase kinase ‘b’ Liver phosphorylase kinase ‘a’ Glycogen phosphorylase ‘b’ Glycogen phosphorylase ‘a’ GLYCOGEN SYNTHESIS- INHIBITION
- 38. ER Membrane depolarisationCa Ca Ca Ca Calmodulin Ca CaCa Ca Protein kinase ‘b’ Protein kinase ‘a’ Glycogen synthase ‘b’ Glycogen synthase ‘a’ GLYCOGENOLYSIS
- 39. Bibliography • Lipincott’s Illustrated Reviews, Biochemistry 5th edition, Richard Harvey, Denise Terrier, Unit II, Chapter 11, Page no: 125- 136 • Jaypee’s Texbook of Biochemistry for medical students, 6th edition, D M Vasudevan, Sreekumari S, Kannan Vaidyanath, Section B, Unit 9, Chapter 9, glycogenolysis, glycogen synthesis, page no 106-112 • McGraw Hills LANGE’s Harper’s Illustrated Biochemistry, R K Murray, D A Bender, P A Weil, 28th edition, Section 11, chapter 19, page no: 157-164 • Wiley-Liss’s Textbook of BIOCHEMISTRY with Clinical Correlations, Thomas M Devlin, 4th edition Chapter 7, carbohydrate metabolism I, major metabolic pathways and their control, page no: 311-334 • Central’s Fundamentals of Biochemistry, A C Deb, 8th edition, Chapter 17, glycogenolysis, clinical orientationof glycogen. Page no: 240-242
- 40. God not only plays dice, he throws them in the corner you can’t see them. - Stephen Hawking