7 glycogen metabolism

1. Glycogen Metabolism

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

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

6. Glycogen Structure

7. Activation of Glucose
UTP
Glucose

8. Activation
of Glucose

9. Glycogen synthaseenzyme catalyses the transfer of
glucose units of UDPG to a pre–existing glycogen
molecule or primer
C
1of UDPG forms a glycosidic bond with C
4of a
terminal glucose residue of glycogen, liberating UDP
When the chain has been lengthened to between 8 and
12 glucose residues, the branching enzymetransfers 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. Glycogenin
(Glycogen primer)
Glycogen primer synthase
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. cAMP(3', 5'-cylic AMP) is
stericallyconstrained by having
a phosphate with ester linkages
to 2 hydroxyls of the same ribose.
Hydrolysis of one of these
linkages (in red), converting
cAMP to 5'-AMP is highly
spontaneous.
The labilityof cAMP to
hydrolysis makes it an excellent
transient signal.
Explore cAMP with Chime.

N
N
N
N
NH
2
O
OHO
HH
H
H
2
C
H
O
P
O
O-
1'
3'
5'4'
2'
cAMP 3',5'–Cyclic AMP ( )

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

19. Insulin Decomposes cAMP
3′-
+
Insulin

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 alphasubunit dissociates
and binds to and activates adenylate cyclase
Adenylate cyclase then converts ATP to cAMP

21. 

22. 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
Activation of cAMP-dependent
protein kinase A (PKA)

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

24. 

25. Structural formulas of four common
intracellular Secondmessengers
cAMP cGMP DAG IP
3

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

27. Regulation of Glycogen Synthesis
Glycogen synthase is directly phosphorylatedby:
Protein kinase A (PKA), which activated by cAMP
Protein kinase C (PKC) or Calmodulin–dependent
protein kinase, which activated by Ca
2+
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 synthasefor UDP–glucose
2.Decreased affinity of synthasefor glucose–6–
phosphate
3.Increased affinity of synthasefor ATPand P
i

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)
+ P
i
glycogen
(n-1)
+ glucose-1-phosphate

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

35. Glycogenolysis

36. Glycogenolysis
(Absent in Muscles)
Phosphoglucomutase

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 AMPis seen only in muscle cells
under extreme conditions of anoxia and ATP
depletion
G6Pinhibits 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
Calciumbinds to calmodulin (subunit of
phosphorylase kinase)
So Calciumions activate phosphorylase kinase
even in the absence of the enzyme phosphorylase
kinase
This allows neuromuscular stimulationby
acetylcholineleading 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
•Ca
2+
•Phospholipase C (PLC)
Glycogen phosphorylase is inhibited by:
•G–6–P
•F–1–P, allosterically

45. Differences Between Liver & Muscle Glycogen
Muscle GlycogenLiver Glycogen
30 Kg1 –1.5 KgTissue Weight
300 g100 g
Glycogen
Amount
1 %10 %
Glycogen
Conc.
Blood Glucose only
Blood Glucose &
Gluconeogenesis
Source
Blood LactateBlood Glucose
Hydrolysis
Product
Used by muscles onlyUsed by all tissues
Energy
produced
Source of Energy for
muscles only
Maintenance of Blood
Glucose
Function

46. Factors Affecting Liver &
Muscle Glycogen
Muscle
Glycogen
Liver
Glycogen
Less Marked IncreaseIncreases greatlyDiet
Little effectDepletionFasting
DepletionLittle effect
Muscular
Exercise

47. Hormonal Regulation of Liver & Muscle Glycogen
Muscle
Glycogen
Liver
Glycogen
GlycogenesisGlycogenesis Insulin
Little increase due to
hyperglycemia
GluconeogenesisGlucocorticoids
Little increase due to
hyperglycemia
Gluconeogenesis
Growth
Hormone
GlycogenolysisGlycogenolysisThyroxine
No EffectGlycogenolysisGlucagon
GlycogenolysisGlycogenolysisAdrenaline

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 glycogenin 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