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Regulation of glycogen metabolism


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Reciprocal regulation of glycogenesis and glycogenolysis

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Regulation of glycogen metabolism

  1. 1. Regulation of Glycogen metabolism NAMRATA CHHABRA, M.D., BIOCHEMISTRY Glycogen metabolism-Part-3 1/14/2017 NAMRATA CHHABRA, M.D. 1
  2. 2. Learning objectives To understand : Purpose of regulation of glycogen metabolism Processes involved and the reciprocal regulation of glycogenesis and glycogenolysis 1/14/2017 NAMRATA CHHABRA, M.D. 2
  3. 3. General mechanisms involved in the regulation of enzyme activities Regulation of enzyme activity Covalent modification Allosteric modification Substrate/product concentration Induction/Repression 1/14/2017 NAMRATA CHHABRA, M.D. 3
  4. 4. Key enzymes involved in the regulation of glycogen metabolism Glycogen synthase- For Glycogenesis Glycogen Phosphorylase Both these enzymes are reciprocally regulated. 1/14/2017 NAMRATA CHHABRA, M.D. 4
  5. 5. Substrate concentration and allosteric modification Substrate- Glucose-6-P  Glycogen Synthase is allosterically activated by glucose-6-P.  High blood glucose concentration leads to elevated intracellular glucose-6-P. When glycolytic pathway is saturated, excess glucose-6-P activates Glycogen synthase and thus is stored as glycogen. High Blood Glucose High Glucose-6-P Saturated Glycolytic pathway Glycogen Synthase v Glycogenesis 1/14/2017 NAMRATA CHHABRA, M.D. 5
  6. 6. Covalent modification- General concepts  Reversible phosphorylation and dephosphorylation  Hormone mediated C-AMP mediated cascade Phosphorylation is mediated by Protein kinase A Dephosphorylation is carried out by Phosphatase Insulin causes dephosphorylation by stimulating Phosphatase and Phosphodiesterase (enzyme that breaks down cAMP) Glucagon causes phosphorylation by stimulating Protein kinase A 1/14/2017 NAMRATA CHHABRA, M.D. 6
  7. 7. Regulation of glycogen synthase by covalent modification Glycogen synthase exists in both phosphorylated or dephosphorylated states Active glycogen synthase a is dephosphorylated and inactive glycogen synthase b is phosphorylated 1/14/2017 NAMRATA CHHABRA, M.D. 7
  8. 8. Covalent modification of glycogen synthase Glycogen synthase a Glycogen synthase b Phosphatase Protein kinase A ATPPi H2O ADP Active Inactive 1/14/2017 NAMRATA CHHABRA, M.D. 8 p
  9. 9. Mechanism of Phosphorylation of glycogen synthase  The cAMP cascade results in phosphorylation of a serine hydroxyl of Glycogen synthase, which promotes transition to the inactive state.  C AMP cascade is active during fasting or starvation and is activated by glucagon or epinephrine. 1/14/2017 NAMRATA CHHABRA, M.D. 9
  10. 10. Implications of Phosphorylation Phosphorylation of Glycogen Synthase promotes the "b" (less active) conformation. The cAMP cascade thus inhibits glycogen synthesis.  Instead of being converted to glycogen, glucose-1-P in liver may be converted to glucose-6-P, and dephosphorylated for release to the blood. 1/14/2017 NAMRATA CHHABRA, M.D. 10
  11. 11. Role of Insulin in Glycogenesis Insulin promotes Glycogenesis. Insulin, produced in response to high blood glucose causes activation of Phosphoprotein Phosphatase resulting in removal of regulatory phosphate residues from Glycogen Synthase enzyme converting it to dephosphorylated/active form. In liver insulin increases the activity of phosphodiesterase, promoting hydrolysis of c AMP terminating hormone action. Insulin thus antagonizes effects of the cAMP cascade induced by glucagon & epinephrine. 1/14/2017 NAMRATA CHHABRA, M.D. 11
  12. 12. ATP Glycogen synthase a Glycogen synthase b C AMP 5’AMP Adenylate cyclase Protein Phosphatase Phosphodiesterase ATP ADP Protein Kinase A H2OPi IG G I IG InsulinGlucagon Glucagon favors phosphorylation thus inhibits glycogenesis Insulin favors dephosphorylation thus stimulates Glycogenesis cAMP Cascade and the role of hormones 1/14/2017 NAMRATA CHHABRA, M.D. 12
  13. 13. Regulation of Glycogenolysis Glycogen Synthase and Glycogen Phosphorylase are reciprocally regulated, by allosteric effectors and by phosphorylation. The control of phosphorylase differs between liver & muscle In the liver the role of glycogen is to provide free glucose for export to maintain the blood concentration of glucose;  In muscle the role of glycogen is to provide a source of glucose 6-phosphate for glycolysis in response to the need for ATP for muscle contraction. 1/14/2017 NAMRATA CHHABRA, M.D. 13
  14. 14. Regulation of Muscle Phosphorylase by allosteric modification Phosphorylase Negative effectors ATP Glucose-6-P Positive effectors AMP Liver phosphorylase is less sensitive to these allosteric modifier. Phosphorylase is inhibited by excess Glucose-P, the product of the reaction sequence. On the contrary, Glycogen synthase is stimulated by excess Glucose-6-P, the substrate of this pathway. Glycogen breakdown is inhibited when ATP and glucose-6- phosphate are plentiful. 1/14/2017 NAMRATA CHHABRA, M.D. 14
  15. 15. Regulation of Glycogenolysis by Covalent Modification (phosphorylation): The cAMP cascade results in phosphorylation of a serine hydroxyl of Glycogen Phosphorylase, which promotes transition to the active state. The phosphorylated enzyme is less sensitive to allosteric inhibitors. Thus, even if cellular ATP and glucose-6-phosphate are high, Phosphorylase will be active. 1/14/2017 NAMRATA CHHABRA, M.D. 15
  16. 16. Phosphorylation of Phosphorylase The enzyme phosphorylase is activated by phosphorylation catalyzed by phosphorylase kinase (to yield phosphorylase a) and Inactivated by dephosphorylation catalyzed by phosphoprotein phosphatase (to yield phosphorylase b), in response to hormonal and other signals. C AMP Phosphorylase Kinase (Active) Protein Kinase A Phosphorylase (Active) 1/14/2017 NAMRATA CHHABRA, M.D. 16
  17. 17. Role of cAMP In Glycogen degradation Increasing the concentration of cAMP activates cAMP-dependent protein kinase, which catalyzes the phosphorylation by ATP of inactive phosphorylase kinase b to active phosphorylase kinase a, which in turn, phosphorylates phosphorylase b to phosphorylase a. In the liver, cAMP is formed in response to glucagon, which is secreted in response to falling blood glucose; muscle is insensitive to glucagon. In muscle, the signal for increased cAMP formation is the action of norepinephrine, which is secreted in response to fear or fright, when there is a need for increased glycogenolysis to permit rapid muscle activity. 1/14/2017 NAMRATA CHHABRA, M.D. 17
  18. 18. ATP Phosphorylase kinase (Inactive) Phosphorylase (Inactive) C AMP 5’AMP Adenylate cyclase Protein Phosphatase Phosphodiesterase ATP ADP Protein Kinase A H2OPi IG G I IG Insulin Glucagon Glucagon favors phosphorylation thus promotes Glycogenolysis Insulin favors dephosphorylation thus inhibits Glycogenolysis cAMP Cascade and the role of hormones Phosphorylase (Active) Phosphorylase kinase (Active) ATP ADP Phosphatase H2O Pi 1/14/2017 NAMRATA CHHABRA, M.D. 18
  19. 19. Role of Ca++ in glycogen degradation Ca++ also regulates glycogen breakdown in muscle. During activation of contraction in skeletal muscle, Ca++ is released from the sarcoplasmic reticulum to promote actin/myosin interactions. The released Ca++ also activates Phosphorylase Kinase, which in muscle includes calmodulin as its δ subunit. Phosphorylase Kinase is partly activated by binding of Ca++ to this subunit. 1/14/2017 NAMRATA CHHABRA, M.D. 19
  20. 20. Role of calcium in muscle degradation Phosphorylase Kinase is partly activated by binding of Ca++ to this subunit. Further activation is brought by phosphorylation. Phosphorylase Kinase Dephosphorylated (inactive) Phosphorylase kinase- Ca++ Partly active Phosphorylase kinase- Ca++ Phosphorylated- active Ca++ ATP 1/14/2017 NAMRATA CHHABRA, M.D. 20
  21. 21. Role of calcium in the activation of phosphorylation kinase Muscle phosphorylase kinase, which activates glycogen phosphorylase, is a tetramer of four different subunits-α, β ,Υ and δ . The α and β subunits contain serine residues that are phosphorylated by cAMP-dependent protein kinase. The δ subunit is identical to the Ca2+-binding protein calmodulin. The binding of Ca2+ activates the catalytic site of the subunit even while the enzyme is in the dephosphorylated b state; the phosphorylated a form is only fully activated in the presence of Ca2+. Phosphorylase Kinase α γδβ Phosphorylase Kinase α β δ γ Protein kinase A Ca++ Phosphatase Ca ++P P Active Enzyme Inactive Enzyme 1/14/2017 NAMRATA CHHABRA, M.D. 21
  22. 22. Role of Insulin in Glycogen degradation Both phosphorylase and phosphorylase kinase are dephosphorylated and inactivated by protein phosphatase. Protein phosphatase is stimulated by Insulin, Therefore Insulin by inhibiting the activation of these enzymes inhibits the overall process of glycogenolysis. 1/14/2017 NAMRATA CHHABRA, M.D. 22
  23. 23. Reciprocal regulation of Glycogenesis and glycogenolysis Glycogen Synthase & Phosphorylase activity are reciprocally regulated At the same time as phosphorylase is activated by a rise in concentration of cAMP (via phosphorylase kinase), glycogen synthase is converted to the inactive form. Thus, inhibition of glycogenolysis enhances net glycogenesis, and inhibition of glycogenesis enhances net glycogenolysis Both processes do not occur at the same time. 1/14/2017 NAMRATA CHHABRA, M.D. 23
  24. 24. Biological significance When the blood glucose is low as in fasting or starvation, the predominant hormones such as Glucagon and epinephrine trigger the C- AMP mediated phosphorylation cascade. In the phosphorylated state glycogen synthase becomes inactive whereas Phosphorylase becomes active, Glycogenesis is switched “off” and Glycogenolysis is switched “on”. Liver glycogen breakdown restores the lowered blood glucose concentration back to normal 1/14/2017 NAMRATA CHHABRA, M.D. 24
  25. 25. Biological significance When the blood glucose concentration is high- Insulin, the main hormone, promotes the dephosphorylated forms of the enzymes by disrupting the c AMP mediated phosphorylation cascade and by stimulating the phosphatase activities. Phosphorylase in the dephosphorylated form becomes inactive whereas the Glycogen synthase in that state becomes active. Hence extra glucose is used for glycogen synthesis and blood glucose concentration is restored back to normal. 1/14/2017 NAMRATA CHHABRA, M.D. 25
  26. 26. Conclusion Glycogenesis and glycogenolysis are reciprocally regulated. Insulin promotes glycogenesis. Glucagon and epinephrine promote glycogenolysis. Glycogenesis is the process of well-fed state. Glycogenolysis is the process of Fasting or starvation. Both these processes are meant for maintaining the blood glucose concentration within the normal range. 1/14/2017 NAMRATA CHHABRA, M.D. 26
  27. 27. Thank you 1/14/2017 NAMRATA CHHABRA, M.D. 27