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glycogen metabolism

glycogen metabolism. glu cose in body fluids, mainly blood Gl yc og e n - liver. ~. 20 g 190 g. ~. Gl yc ogenol ysi s. ~. 24 hrs starvation. after. Glu coneogenes is. Glucose homeostasis. Carbohydrate/glucose reserve „Buffer role” in the maintenence of blood glucose level.

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glycogen metabolism

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  1. glycogen metabolism

  2. glucose in body fluids, mainly blood Glycogen - liver ~ 20 g 190 g ~ Glycogenolysis ~ 24 hrs starvation after Gluconeogenesis Glucose homeostasis Carbohydrate/glucose reserve „Buffer role” in the maintenence of blood glucose level

  3. Structure of glycogen

  4. Glycogen synthesis

  5. G-6-P - G-1-P conversion DIPF: diisopropylfuorophosphate - inhibitor

  6. Activated glucose

  7. Reaction is pulled in the forward direction by the hydrolysis of PPi

  8. UDP-glucose pyrophosphorylase

  9. Primer is required

  10. glycogenin • Autocatalytic activity for glycosylation • Human glycogenin gene- 1 muscle, -2 liver • 5 exons • 0.3% of glycogen is protein • Glycogenin content determines the cellular glycogen content

  11. Glycogen branching enzyme: glycosyl (4,6) transferase, -more soluble glycogen -more non reducing terminal residues increased rate of metabolism

  12. Glycogenesis

  13. Energy balance of glycogenesis for one glycosyl unit G-6-P + ATP + glycogen (n) + H2O Glycogen (n+1) + ADP + 2Pi

  14. Glycogen degradation

  15. Phosphorolysis = cleavage of a bond by Pi Energetically advantageous – released sugar is phosphorylated Glycogen phosphorylase

  16. Debranching enzyme Single polypeptide chain

  17. Glycogenosis = glycogen storagedisease • Targets: liver(blood glucose homeostasis – hypoglycaemia, hepatomegaly) muscle (ATP production, muscle contraction convulsions, weakness, unable for muscle work)

  18. Glucose-6 phosphatase enzyme system in the ER membrane

  19. ADP increases during exercise in McArdle disease measured byNMR

  20. Glycogen phosphorylase Muscle dimer or tetramer, Ser 14 phosphorylation/monomer AMP binding site Liver Glucose sensor function Regulated by allosteric interactions and Reversible phosphorylation

  21. Glycogen phosphorylase Pi binding site PLP: pyridoxal phosphate – each catalytic site contains PLP group

  22. PLP - Schiff base linkage at active site of phosphorylase

  23. active usually inactive not phosphorylated phosphorylated

  24. Equilibrium favors Equilibrium favors

  25. Allosteric binding site for nucleotides Transition is controlled by the energy charge of the muscle cell

  26. Glycogen phosphorylase • Phosphorylase a is fully active regardless of the levels of ATP/AMP, G-6-P • Phosphorylase bis usually inactive under physiological circumstances because of the inhibitory effect of ATP and G-6-P

  27. Allosteric binding site for glucose – glucose sensor function – only in liver inactive Under physiological conditions there is no AMP dependent regulation

  28. Activation of phosphorylase kinase e.g. epinephrine δ subunit: calmodulin – calcium sensor

  29. Glycogen synthase • 9 sites for phosphorylation • PKA and other protein kinases can phosphorylate the enzyme • Phosphorylation converts the activea form of the enzyme to inactiveb form

  30. Reciprocal regulation in glycogen metabolism

  31. PP1: protein phosphatase 1 • PP1 inactivates phosphorylase kinase and phosphorylase a • PP1 decreases glycogen breakdown • PP1 converts glycogen synthase b to much more active a form • PP1 accelerates glycogen synthesis

  32. PP1: protein phosphatase 1 Rgl: glycogen binding subunit PP1 is active, when associated with glycogen Rgl can be phosphorylated by PKA - causes dissociation from PP1 - inactive

  33. Rgl can be phosphorylated by PKA - causes dissociation from PP1 - inactive Rgl can be phosphorylated by insulin sensitive protein kinase - causes association to PP1 - active

  34. Blood glucose regulates liver glycogen metabolism

  35. Only in liver Muscle phosphorylase is unaffected by glucose

  36. Signal amplification

  37. Regulation of blood glucose level. Hyperglycaemia -1 • Liver increased glucose uptake – GLUT2 Glucokinase – „extra glucose” Increased glycogenesis – insulin; PP1 – glycogen synthase Decreased glycogenolysis – glucose sensor function – glycogen phosphorylase PDH active – increased fatty acid synthesis

  38. Regulation of blood glucose level. Hyperglycaemia -2 • Peripheral tissues pancreas increased glucose uptake – GLUT2 Glucokinase – insulin secretion muscle, adipocytes GLUT4 increased number in membranes Increased glycogenesis Decreased glycogenolysis increased glycolysis – PFK1

  39. Regulation of blood glucose level. Hyperglycaemia -3 Long term effects Decreased amount of PEPCK – decrease in gluconeogenesis

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