1. Glycogen Metabolism

2.  Glycogenesis and glycogenolysis occur in
the cytoplasm of cells

3. Glycogenesis &
Glycogenolysis
Step 2
UDP-glucose pyrophosphorylase
Step 3 P~Pi
Step 4
Glycogen synthase
Branching enzyme

6. Glycogen Structure

7. Activation of Glucose
UTP
Glucose

8. Activation
of Glucose

9.  Glycogen synthase enzyme catalyses the transfer of
glucose units of UDPG to a pre–existing glycogen
molecule or primer
 C1 of UDPG forms a glycosidic bond with C4 of a
terminal glucose residue of glycogen, liberating UDP
 When the chain has been lengthened to between 8 and
12 glucose residues, the branching enzyme transfers a
part of the 1,4–chain to a neighboring chain to form a
1,6–linkage, thus establishing a branching point in the
molecule

10. Glycogen Synthase Enzyme
& Branching Enzyme

11. Glycogen primer synthase
Glycogenin
(Glycogen primer)
autocatalysis

12. Glycogen primer
Glycogen primer synthase

15. Regulation of Glycogenesis
 Glycogen synthase is the key enzyme of glycogenesis
 It is present in two inter-convertible forms:
 Synthase D, inactive (Dependent), phosphorylated
 It is dependent on the presence of G6P
 Synthase I, active (Independent), which is
dephosphorylated and independent on the
presence of glucose 6–phosphate
 Synthase I is converted to the inactive synthase D by
phosphorylation by protein kinase enzyme, with ATP
as phosphate donor
 The protein kinase only acts in the presence of cAMP

16. Glycogenesis
 Stimulated after carbohydrate meal, due to
increased insulin
 Glycogen synthase activated allosterically
by Glucose–6–phosphate & ATP
 Inhibited during fasting, due to increased
secretion of adrenaline & glucagon
 Inhibited also by thyroxin

17. cylic AMP) is
trained by having
3',5'–Cyclic AMP (cAMP ) NH2
ith ester linkages
N
of the same ribose. N
one of these N
N
d), converting
MP is highly H2 O
5' C 4'
H H 1'
O
H 3' 2' H
cAMP to P O OH
kes it an excellent O
O-
al.
P with Chime.

18. The conversion of ATP to cyclic
AMP releases pyrophosphate
Adrenaline
&/or
Glucagon
+
(P~Pi(
3′,5′-cAMP

19. Insulin Decomposes cAMP
Insulin
+
3′-

20. Activation of cAMP-dependent
protein kinase A (PKA)
 Glucagon activates it's cell-surface receptor
 This activation is coupled to the activation of a
receptor-coupled G–protein (GTP–binding and
hydrolyzing protein)
 G–protein is composed of 3 subunits (, , )
 Upon activation the alpha subunit dissociates
and binds to and activates adenylate cyclase
 Adenylate cyclase then converts ATP to cAMP

21. 

22. Activation of cAMP-dependent
protein kinase A (PKA)
 PKA is cAMP-dependent protein kinase
 PKA is composed of 2 catalytic & 2 regulatory subunits
 The cAMP binds to the regulatory subunits of PKA
leading to dissociation of the catalytic subunits, so the
catalytic subunits become active
 The dissociated catalytic subunits phosphorylate
numerous substrate using ATP as phosphate donor

23. Activation of
Protein kinase A
C cAMP C
R R
C
C R R
2 Catalytic & 2 Regulatory subunits

24. 

25. Structural formulas of four common
intracellular Second messengers
cAMP cGMP DAG IP3

26. Regulation of Glycogen Synthesis
 Briefly, glycogen synthase I (active form)
when phosphorylated, becomes much less
active and requires glucose–6–phosphate to
restore its activity
 PKA also phosphorylates glycogen synthase
directly

27. Regulation of Glycogen Synthesis
 Glycogen synthase is directly phosphorylated by:
 Protein kinase A (PKA), which activated by cAMP
 Protein kinase C (PKC) or Calmodulin–dependent
protein kinase, which activated by Ca2+ ions or DAG
 DAG is formed by receptor–mediated hydrolysis of
membrane phosphatidylinositol disphosphate (PIP2)

28. • Phosphorylation of Glycogen Synthase
leads to:
1. Decreased affinity of synthase for UDP–glucose
2. Decreased affinity of synthase for glucose–6–
phosphate
3. Increased affinity of synthase for ATP and Pi

29. Glycogenolysis
 It is the breakdown of glycogen into glucose in
liver or into lactic acid in muscles
 In liver, glycogenolysis maintains the blood
glucose level during fasting for less then 18
hours
 In muscles, glycogenolysis followed by
glycolysis supply the contracting muscle with
energy during muscular exercise
 Site: Cytoplasm of cells

31. Glycogen Catabolism (Breakdown)
• Glycogen Phosphorylase
catalyzes phosphorolytic
cleavage of the  (1 4)
glycosidic linkages of
glycogen, releasing
glucose-1-phosphate
Glycogen (n) + Pi  glycogen (n-1) + glucose-1-phosphate

32. Glycogenolysis
1. Glycogen phosphorylase acts at the 1,4–glycosidic
linkages yielding glucose–1–P. It stops when there are
only four glucose units away from a branch point
2. Glucan transferase transfers a trisaccharide unit from
one side to the other, thus exposing the 1,6–linkage
(branch point)
3. Debranching enzyme acts on the 1,6–linkage to
liberate a free glucose residue

35. Glycogenolysis

36. Glycogenolysis
Phosphoglucomutase
(Absent in Muscles)

37. Regulation of Glycogenolysis
 Phosphorylase is the key enzyme of glycogenolysis
 There are 2 types of phosphorylase enzyme
 Active form: phosphorylase a, which is
phosphorylated, so known as phospho-
phosphorylase
 Inactive form: phosphorylase b, which is
dephosphorylated, so known as dephospho-
phosphorylase

38. Regulation of Glycogenolysis
 Phosphorylase b is converted to phosphorylase a
by the enzyme phosphorylase b kinase, with ATP
as phosphate donor
 Phosphorylase b kinase is activated by the enzyme
protein kinase which requires cAMP for its activity
 cAMP is increased by glucagon (in liver) and
adrenaline (in liver and muscle)

39. Regulation of Glycogenolysis
 Glycogen phosphorylase is also regulated by
allosteric effectors:
 Activation by AMP is seen only in muscle cells
under extreme conditions of anoxia and ATP
depletion
 G6P inhibits glycogen phosphorylase by binding
to the AMP allosteric site, to ensure that glycogen
is not wasted if the cells have sufficient energy

40. Regulation of Glycogenolysis
 Activation of glycogen degradation during muscle
contraction by calcium
 Rapid need of ATP increases nerve impulses,
leading to membrane depolarization, which
promote Ca release from the sarcoplasmic
reticulum into the sarcoplasm of muscle cells

41. Regulation of Glycogenolysis
 Calcium binds to calmodulin (subunit of
phosphorylase kinase)
 So Calcium ions activate phosphorylase kinase
even in the absence of the enzyme phosphorylase
kinase
 This allows neuromuscular stimulation by
acetylcholine leading to increased glycogenolysis
in the absence of receptor stimulation

43. Regulation of Glycogen
Phosphorylase

44. Regulation of Glycogen Phosphorylase
 Glycogen phosphorylase is activated by:
• cAMP
• AMP, allosterically
• Ca2+
• Phospholipase C (PLC)
 Glycogen phosphorylase is inhibited by:
• G–6–P
• F–1–P, allosterically

45. Differences Between Liver & Muscle Glycogen
Liver Glycogen Muscle Glycogen
Tissue Weight 1 – 1.5 Kg 30 Kg
Glycogen
100 g 300 g
Amount
Glycogen
10 % 1%
Conc.
Blood Glucose &
Source Blood Glucose only
Gluconeogenesis
Hydrolysis
Blood Glucose Blood Lactate
Product
Energy
Used by all tissues Used by muscles only
produced
Maintenance of Blood Source of Energy for
Function
Glucose muscles only

46. Factors Affecting Liver &
Muscle Glycogen
Liver Muscle
Glycogen Glycogen
Diet Increases greatly Less Marked Increase
Fasting Depletion Little effect
Muscular
Little effect Depletion
Exercise

47. Hormonal Regulation of Liver & Muscle Glycogen
Liver Muscle
Glycogen Glycogen
Insulin Glycogenesis Glycogenesis
Little increase due to
Glucocorticoids Gluconeogenesis
hyperglycemia
Growth Little increase due to
Gluconeogenesis
Hormone hyperglycemia
Thyroxine Glycogenolysis Glycogenolysis
Glucagon Glycogenolysis No Effect
Adrenaline Glycogenolysis Glycogenolysis

48. Glycogen Storage Diseases (GSD)
• Glycogen storage diseases are inborn errors of
glycogen metabolism (genetic diseases)
• It is characterized by the storage of abnormal
amounts of glycogen in the body
• There are five different types of these diseases
depending on the enzyme missing

49. Glycogen Storage Diseases (GSD)
• All people who are born with GSD are unable to
properly metabolize or break down glycogen
• People with GSD have the ability to use sugar
stored as glycogen, but are unable to use the
stores to provide the body with energy during
fasting or exercise

50. Thanks