Slides include Glycogenesis and Glycogenolysis along with regulation and Glycogen Storage Disease

1. 1
By:
Akanksha Dubey
Assistant Professor
People’s College of Medical Sciences and Hospital Bhopal

2. Glycogen was discovered by Claude Bernard (he
discovered that liver can generate reducing sugar)
Carl and Gerty Cori were awarded Nobel prize in
1947, for their work on glycogen degradation.
Glycogen is a Multi branched polysaccharides of
glucose that serves as a energy storage form in
human, animals, bacteria and plants(which are
devoid of chlorophyll system s/a yeast, fungi)
2

3. It is main storage form of glucose in the body and
readily mobilized also hence c/a Animal starch
It is Dextrorotatory, formation is k/a Glycogenesis
and Degradation is k/a Glycogenolysis
Most of the glucose residues in glycogen are linked
by α-1,4-glycosidic bonds and Branches residue are
created by α-1,6-glycosidic bonds.
It is a polymer of D Glucose units hence resemble
amylopectin
3

4. Glycogen and TG serve as long term energy
reserve of the body.

5. Glycogen is a polymer of glucose residues linked by
 a(14) glycosidic bonds, mainly
 a(16) glycosidic bonds, at branch points.
H O
OH
H
OHH
OH
CH2OH
H
O H
H
OHH
OH
CH2OH
H
O
HH H O
O
H
OHH
OH
CH2
H
H H O
H
OHH
OH
CH2OH
H
OH
HH O
O
H
OHH
OH
CH2OH
H
O
H
O
1 4
6
H O
H
OHH
OH
CH2OH
H
H H O
H
OHH
OH
CH2OH
H
H
O
1
OH
3
4
5
2
glycogen

6. Glycogen is present in the cytosol in the form of granules ranging in
diameter from 10 to 40 nm.

7. Why branching ?
 The highly branched structure of glycogen provides a
large number of sites (terminal residues- non reducing
ends)for synthesis and degradation of glycogen,
permitting rapid storage of extra glucose after meals or
release of glucose 1-phosphate for muscle activity.

9. Functions of Glycogen
1. Glycogen is the storage form of carbohydrates in the
human body. The major sites of storage are liver
and muscle.
2. When blood glucose level falls, liver glycogen is
largely concerned with storage and supply of
Glucose-1-phosphate which is converted to Glucose for
maintenance of blood glucose level between the
meals.

10. 3. Muscle glycogen is responsible for providing
energy to muscle itself through Glycolysis.
Muscle glycogen can’t contribute to blood glucose
level. The function of muscle glycogen is to act as
reserve fuel for muscle contraction.
4. All the enzymes related to glycogen metabolism
are cytoplasmic.

11. It is stored mainly in liver and
muscle
The liver content of glycogen is
greater than that of muscle, Since the
muscle mass of the body is
considerably greater than that of the
liver, about three-quarters of total
body glycogen is in muscle

12. Percentage of
Tissue Weight
Tissue Weight Body Content
Liver glycogen
4-6 %
1.8 kg 72-108 gm
Muscle
glycogen
0.7 -1 % 35 kg 245-350gm
Extracellular
glucose
0.1 % 10 L 10 gm

13. Why Glycogen is Used as Reserve form of
energy
Glycogen serves as a buffer to maintain blood-glucose
levels.Glucose is the only fuel used by the brain, except
during prolonged starvation.
The glucose from glycogen is readily mobilized and
is therefore a good source of energy for sudden,
strenuous activity.

14. Being insoluble it exerts no Osmotic Pressure and so
do not disturb the intracellular fluid content (same
amount of glucose will triple the osmotic pressure
and cells will burst)
Glucose can provide energy in anaerobic condition also.
Fatty acids can not cross blood barrier hence glucose is
only source of energy to brain

15. Glycogen
Metabolism
Glycogenesis Glycogenolysis

16. Glycogenesis is the synthesis of glycogen from glucose.
Glycogenesis mainly occurs in Muscle and Liver.
Muscle glycogen provides a readily available source
of glucose for glycolysis within the muscle itself.
Liver glycogen functions to store and export glucose to
maintain blood glucose between meals/Fasting state

18. Steps of Glycogenesis
 Polymerization of glucose into Glycogen is k/a
Glycogenesis.
 Thermodynamically it is Endergonic reaction which
require ATP and UTP
The following enzyme reactions occur in glycogen synthesis:
1. Synthesis of an Activated Precursor, UDP-glucose, by
UTP: Glucose-1-phosphate Uridyltransferase
2. Initiation of Glycogen Synthesis by Glycogenin
3. Introduction of branches by Branching Enzyme
4. Chain elongation by Glycogen Synthase
5. Repetition steps 3 and 4

19. Hexokinase in Muscle Glucokinase in
liver , Magnesium is required is required
in both the steps
PPi formed is converted to inorganic
phosphatase(pi) by Pyrophosphatase
enzyme, which makes reaction
Irreversible
1 UTP is utilized here
UDP Glucose is active form of Glucose,
C1 of UDP-G forms glycosidic bond with
C4 of glycogenin to form Glycogen
Primer

20. Glycogen primer receives 7-8 glucose units
on its own this reaction is catalyzed by
glycogenin itself and after that reaction is
catalyzed by Glycogen synthase(Key
enzyme)
Glycogen Synthase which adds glucose
units to primer upto 11 units.
UDP is converted to UTP by Nucleoside
Diphosphate Kinase which is further
reutilized in reaction
After 11 glucose units Branching enzyme is
introduced which transfer 6 glucose units
to branching point.(alpha 1,4 to alpha 1,6)
Chain elongation by Glycogen Synthase
and Branching by branching enzyme is
repeated

21. Glycogenin initiates glycogen synthesis. It is primer for new chain
synthesis and enzyme too that catalyze its synthesis.
Glycogenin is an enzyme that catalyzes attachment of a glucose molecule to
one of its own tyrosine residues.
It is homodimer of 37 KDa which adds up only 7-8 residues of glucose after
that chain is elongated by Glycogen synthase
Tyr active site
active site Tyr
Glycogenin dimer

22.  The overall reaction of the glycogen synthesis for the
addition of each glucose residue is
(Glucose)n + Glucose + 2ATP ------> (Glucose)n*1 +2ADP+Pi
 Of the Two ATP utilized, one is required for the
phosphorylation of glucose while the other is needed
for conversion of UDP to UTP.

23. Purpose of Glycogenolysis
 The controlled breakdown of glycogen and release of
glucose increase the amount of glucose between
meals. Hence, glycogen serves as a buffer to
maintain blood-glucose levels.
 Glycogen's role in maintaining blood glucose levels is
especially important because glucose is virtually the
only fuel used by the brain, except during prolonged
starvation.

24.  The glucose from glycogen is readily mobilized and
is therefore a good source of energy for sudden,
strenuous activity.
 Unlike fatty acids, the released glucose can provide
energy in the absence of oxygen and can thus supply
energy for anaerobic activity.

25. GLYCOGENOLYSIS
 The degradation of stored glycogen in liver and muscle
constitutes Glycogenolysis.
 The pathways for the synthesis and degradation of
glycogen are not reversible.
 An independent set of enzymes present in the cytosol
carry out Glycogenolysis.
 Glycogen is degraded by breaking α 1 ,4- and α 1,6-
Glycosidic bonds

26. The alpha 1,4-glycosidic bonds
(from the non-reducing ends) are
cleaved sequentially by the enzyme
Glycogen Phosphorylase to yield
glucose 1-phosphate. This process-
called phosphorolysis and this
continues until four glucose residues
remain on either side of branching
point (a-1,6glycosidic linkage).
The glycogen so formed is known
as limit dextrin which cannot be
further degraded by Phosphorylase.
The branches of glycogen are
cleaved by two enzyme activities
present on a single polypeptide
called Debranching Enzyme,
hence it is a Bifunctional Enzyme.
Alpha 1,4 transferase activity
removes a fragment of three or
four glucose residues attached at a
branch and transfers them to
another chain.

27. Alpha 1,6 Glucosidase breaks the alpha1,6
bond at the branch with a single glucose
residue and releases a free glucose.
The remaining molecule of glycogen is again
available for the action of Phosphorylase
and debranching enzyme to repeat the
reactions stated in 1 and 2.
Through the combined action of glycogen
Phosphorylase and debranching enzyme
glucose 1-phosphate and free glucose in a ratio
of 8 : 1 are produced. Glucose 1 -phosphate is
converted to glucose 6-phosphate by the
enzyme phosphoglucomutase
The fate of glucose 6-phosphate depends on
the tissue. The liver, kidney and intestine
contain the enzyme glucose 6-phosphatase
that cleaves glucose 6-phosphate to glucose.
This enzyme is absent in muscle and brain,
hence free glucose cannot be produced from
glucose 6-phosphate in these tissues. In the
peripheral tissues, glucose 6-phosphate
produced by Glycogenolysis will be used for
glycolysis

29. MULTIPLE FATES OF GLUCOSE-6-PHOSPHATE

30. Lysosomal glycogen disposal
A small amount (1–3%) of glycogen is continuously
degraded by the lysosomal enzyme, α ( 1 → 4 ) -
Glucosidase ( acid maltase ).
The purpose of this pathway is unknown.
In liver cells, approximately 10% of all glycogen particles
are found inside Lysosomes , where they undergo slow
degradation by acid maltase.

31. However, a deficiency of this enzyme causes
accumulation of glycogen in vacuoles in the Lysosomes,
resulting in the serious glycogen storage disease Type
II: Pompe's disease
Type II: Pompe's disease is the only glycogen storage
disease that is a lysosomal storage disease

32. Regulation of Glycogenesis and Glycogenolysis
 A good coordination and regulation of glycogen synthesis
and its degradation are essential to maintain the blood
glucose levels.
 Glycogenesis and Glycogenolysis are, respectively,
controlled by the enzymes glycogen synthase and
glycogen Phosphorylase.
 Regulation of these enzymes is accomplished by three
mechanisms

33. Allosteric regulation
Hormonal regulation
Influence of calcium

34. Allosteric regulation of glycogen
metabolism
 There are certain metabolites that allosterically regulate
the activities of Glycogen Synthase and Glycogen
Phosphorylase.
 The control is in such a way that glycogen synthesis is
increased when substrate is available and energy levels
are high(ATP) and Glycogenolysis is enhanced when
glucose concentration and energy levels are low.

36.  In a well-fed state, the availability of
glucose-6-phosphate is high which allosterically activates
glycogen synthase for more glycogen synthesis.
 On the other hand, glucose 6-phosphate and ATP
allosterically inhibit glycogen Phosphorylase.
 Free glucose in liver also acts as an Allosteric inhibitor
of glycogen Phosphorylase.

39. Hormonal regulation of glycogen metabolism
 The hormones, through a complex series of reactions,
bring about covalent modification, namely
Phosphorylation and Dephosphorylation of enzyme
proteins which, ultimately control glycogen synthesis or
its degradation

43. Regulation of glycogen synthesis by cAMP
 The Glycogenesis is regulated by glycogen synthase.
 This enzyme exists in two forms
a) Glycogen Synthase ‘a’: Dephosphorylated (Active)
b) glycogen synthase 'b’: Phosphorylated (Inactive)
Glycogen synthase 'a‘ (active) can be converted to 'b' form
(inactive) by phosphorylation.

44. Glycogen degradation is not just the
reverse of glycogenesis
Glycogenesis
 Formation of activated
precursor UDP Glucose
 Initiation by Glycogenin
 Branching by branching
enzyme
 Elongation by Glycogen
Synthase
 Repetition of above 3 and 4
steps
Glycogenolysis
 Depolymerization of linear strands
by Phosphorylase
 Debranching enzyme activity
 Repetition of above steps
 Conversion of Glucose-1-P to
Glucose-6-P
 Conversion of Glucose-6-P to
free Glucose

45.  These are a group of genetic diseases that result from a
defect in an enzyme required for glycogen synthesis or
degradation.
 They result either in formation of glycogen that has an
abnormal structure, or in the accumulation of excessive
amounts of normal glycogen in specific tissues as a result of
impaired degradation.
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46.  A particular enzyme may be defective in a single
tissue, such as liver (resulting in hypoglycaemia) or
muscle (muscle weakness), or the defect may be more
generalized, affecting liver, muscle, kidney, intestine,
and myocardium.
 The severity of the glycogen storage diseases (GSDs)
ranges from fatal in infancy to mild disorders that are
not life-threatening.

47. Glycogen Storage Disease Type-I
 It is also called Von Gierke's Disease.
 Most common type of glycogen storage disease is type I.
 Incidence is 1 in 100,000 live births.
 Patients with Type І GSD are unable to release glucose
from glycogen due to the deficiency of Glucose-6-
Phosphatase and hence with time glycogen builds up in
the liver.

48. Characterized by
 massive enlargement of liver (hepatomegaly),
 growth retardation,
 fasting hypoglycemia,
 increased lactic acid concentrations in the blood (due to
excessive glycolysis),

49.  Hyperuricemia(Glucose-6-phosphate is accumulated, so
it is channelled to HMP shunt pathway producing more
ribose and more nucleotides.
 Purines are then catabolised to uric acid, leading to
hyperuricemia

51. Type І b
 has been identified as a defect in the glucose–6–
phosphatase transport system.
 Very rare

52. Type II
 Called as Pompe disease
 Deficiency of Lysosomal α-1,4 and α 1,6 glucosidase (Acid
Maltase)
 Primary organ involved: all organs with Lysosomes
 A homozygous deficiency of acid maltase disrupts lysosomal
glycogen degradation and results in glycogen accumulation.
 Skeletal and heart muscle are more strongly affected than the liver.
Glycogen accumulation interferes with muscle cell function and
contraction, and heart failure leads to death.

53.  The condition, can vary in severity; complete lack of
enzyme activity becomes manifest in infants, whereas
mutations that reduce but do not completely inactivate
the enzyme will cause milder disease with onset
deferred to later childhood or adolescence.
 The disease can be treated with enzyme replacement
therapy.

54. Type III
 Limit Dextrinosis/ Forbes's /Cori’s Disease
 Primary Organ involved: liver, skeletal muscle and heart
 Deficiency of Amylo-1, 6–Glucosidase (Debranching
enzyme) results in storage of an abnormal form of
glycogen.
 Accumulation of abnormal glycogen having short chain
glycogen, hypoglycemia

55. Type IV
Anderson’s Disease/Amylopectinosis
Absence of Branching Enzyme (Amylo 1,4 to 1,6
transglucosidase)
Primary Organ involve: liver
These patients experience muscle pain, cramps, fatigue
and muscle tenderness.
 accumulation of abnormal glycogen, having few
branches, early death due to liver and cardiac failure

56. Type V
 McArdle Disease
 Absence of Muscle Glycogen Phosphorylase
 Primary Organ involve: Skeletal Muscle(glucose cannot
be released from the glycogen stored in skeletal muscles
for energy)
 These patients experience muscle pain, cramps, fatigue
and muscle tenderness.
 With the breakdown of muscle and the release of
myoglobin, myoglobinuria may develop.

57. Type VI
 Type VI GSD also known as Hers’ disease is a rare
disorder due to the deficiency of Liver Phosphorylase
 Primary organ involved is liver
 Enlargement of liver due to increased deposit of
glycogen, ketosis and mild hypoglycemia are seen.

58. Type VII
 Tarui’s Disease
 Deficiency of Phosphofructokinase in RBC and Muscle
 Primary organ involved : Muscle and RBC
 Patients have deposition of abnormal glycogen in muscle.
 Muscular pain, cramps, decrease serum lactate after
exercise, and hemolytic anaemia

60. Glycogen represents the principal storage form of
carbohydrate in the body, mainly in the liver and muscle.
Glycogen is synthesized from glucose by the pathway of
glycogenesis.
It is broken down by a separate pathway, glycogenolysis.
Glycogenolysis leads to glucose formation in liver and
lactate formation in muscle owing to the respective presence
or absence of glucose 6-phosphatase.
60

61. Cyclic AMP integrates the regulation of glycogenolysis
and Glycogenesis by promoting the simultaneous
activation of Phosphorylase and inhibition of glycogen
synthase.
Insulin acts reciprocally by inhibiting Glycogenolysis and
stimulating Glycogenesis.
Inherited deficiencies in specific enzymes of glycogen
metabolism in both liver and muscle are the causes of
glycogen storage diseases.