1. glycogen metabolism

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

5. Structure of glycogen

6. Glycogen synthesis

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

8. Activated glucose

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

10. UDP-glucose pyrophosphorylase

11. Primer is required

13. 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

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

16. Glycogenesis

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

18. Glycogen degradation

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

20. Debranching enzyme
Single
polypeptide chain

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

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

27. ADP increases during exercise in McArdle disease measured byNMR

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

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

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

33. active
usually inactive
not phosphorylated
phosphorylated

34. Equilibrium
favors
Equilibrium
favors

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

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

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

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

40. Glycogen synthase 9 sites for phosphorylation
PKA and other protein kinases can phosphorylate the enzyme
Phosphorylation converts the active a form of the enzyme to inactive b form

41. Reciprocal regulation in glycogen metabolism

42. 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

43. 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

44. 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

45. Blood glucose regulates liver glycogen metabolism

46. Only in liver
Muscle phosphorylase is unaffected by glucose

47. Signal amplification

48. 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

49. 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

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

51. Regulation of blood glucose level. Hypoglycaemia
liver
Increased gluconeogenesis
Increased glycolysis

52. Regulation of blood glucose level. Hypoglycaemia
newborns
Limited ketone body synthesis
Brain/body rate – Increased glucose demand
PEPCK is not induced, gluconeogenesis is not enough
Glycogen storage is limited
Glucokinase, G-6-P-ase are not induced