Reactions and regulation of glycogenesis and glycogenolysis

1. Glycogen Metabolism
R. C. Gupta
Professor and Head
Department of Biochemistry
National Institute of Medical Sciences
Jaipur, India

2. Glycogen is the form in which carbohydrates
are stored in animals
The function of glycogen is analogous to
that of starch in plants
Therefore, it is also known as animal starch
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3. Glycogen is a branched macromolecule
made up of a large number of glucose units
In linear portions, glucose units are joined
by a-1,4-glycosidic bonds
Branches arise from linear portions by
a-1,6-glycosidic bonds
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4. Glycogen
Reducing end
Branches
a-1,4-Glycosidic bond
a-1,6-Glycosidic bond

5. Glycogen is synthesized from glucose
Synthesis of glycogen is known as
glycogenesis
Glycogen is broken down to glucose
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Breakdown of glycogen is known as
glycogenolysis

6. Glycogenesis is the pathway for synthesis
of glycogen
It is a mechanism by which excess glucose
is stored in the tissues
It occurs in almost all the tissues but the
predominant sites are liver and muscles
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Glycogenesis

7. After a meal rich
in carbohydrate։
Glycogenesis occurs rapidly in liver
and muscles
Glycogen content of liver may go up
to 5% of wet tissue weight
Glycogen content of muscles can go
up to 1% of wet tissue weight

8. Glycogenesis occurs in the cytosol
Glycogenesis begins with a small glycogen
molecule known as glycogen primer
The core of the primer is made up of a
protein, glycogenin
A glucose molecule is attached to
glycogenin via a tyrosine residue

9. Successive glucose units are added to the
primer until a large glycogen molecule is
formed
Glucose is first converted into glucose-6-
phosphate
Then, glucose-6-phosphate is converted into
glucose-1-phosphate by phosphoglucomutase

11. Glucose-1-phosphate reacts with uridine
tri-phosphate (UTP) to form uridine
diphosphate glucose (UDPG)
This reaction is catalysed by UDPG pyro-
phosphorylase

13. Inorganic pyrophosphate is immediately
hydrolysed into inorganic phosphate
Due to release of free energy, this
reaction is functionally irreversible
PPi + H2O
Inorganic
pyrophosphatase
2 Pi

14. UDPG reacts with glycogen primer
UDP is released and glucose is added to
the glycogen primer
Glycogen primer having n glucose
units would have n+1 glucose units after
the reaction

15. Carbon 1 of the new glucose unit forms a
glycosidic bond with carbon 4 of the last
glucose unit
The reaction is catalysed by glycogen
synthetase
UDPG+(Glucose)n
Glycogen
synthetase
UDP+(Glucose)n+1

16. Addition of glucose units to the glycogen
primer continues until the chain contains
about eleven glucose units
Then, amylo-1,4  1,6-transglucosidase
detaches a fragment of 6-7 glucose units
from the growing end

18. The two branches start growing again by
addition of glucose units by a-1,4-glycosidic
bonds catalysed by glycogen synthetase
When the branches contain about 11
glucose units, branching enzyme acts again
and creates more branches

19. The process of lengthening and branching
continues until a large and highly branched
glycogen molecule is formed
Two branch points are separated by 8-12
glucose units

20. Regulation
The regulatory enzyme is glycogen synthetase
which is regulated by covalent modification
The covalent modification is addition or
removal of phosphate
The enzyme exists in two forms – glycogen
synthetase a and glycogen synthetase b

21. Glycogen synthetase a is the dephospho-
rylated and active form of the enzyme
Glycogen synthetase b is the phosphorylated
and inactive form
Addition of phosphate converts glycogen
synthetase a into glycogen synthetase b
Removal of phosphate converts glycogen
synthetase b into glycogen synthetase a

22. Phosphate is added to glycogen synthe-
tase a by protein kinase A
Phosphate is removed from glycogen
synthetase b by protein phosphatase-1
Protein kinase A and protein phosphatase-
1 are regulated by cAMP
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23. Intracellular concentration of cAMP is
regulated by some hormones
So, the ultimate regulators of glycogenesis
are epinephrine, glucagon and insulin
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Epinephrine and glucagon increase the
concentration of cAMP
Insulin decreases the concentration of
cAMP

25. cAMP is the regulator of protein kinase A
(cAMP-dependent protein kinase)
Protein kinase A is a tetramer made up of two
regulatory (R) and two catalytic (C) subunits
The tetrameric form is inactive as regulatory
subunits inhibit the catalytic subunits

26. When cAMP concentration rises, two cAMP
molecules bind to each regulatory subunit
The tetramer dissociates into monomers
The catalytic subunits are no longer inhibited
by regulatory subunits

28. Active protein kinase A phosphorylates
glycogen synthetase
Phosphorylation converts active glycogen
synthetase a into inactive glycogen
synthetase b
Active protein kinase A also phospho-
rylates a protein known as inhibitor-1

29. The phosphorylated form of inhibitor-1 is
active
It inhibits protein phosphatase-1
This decreases the conversion of
glycogen synthetase b into glycogen
synthetase a

30. Thus, active protein kinase A:
Increases the conversion of active
glycogen synthetase into its inactive form
Decreases the conversion of inactive
glycogen synthetase into its active form
The net result is a decrease in glycogenesis

31. The reverse occurs when the concentration
of cAMP is low
The rate of glycogenesis is increased
Thus, the rate of glycogenesis is regulated
by the intracellular concentration of cAMP

33. In muscles
Glycogenesis is
regulated mainly
by epinephrine
and insulin
In liver
Glycogenesis is
regulated mainly
by glucagon
and insulin

34. Glycogenolysis is breakdown of
glycogen
It is not a reversal of glycogenesis but
is a separate pathway
Glycogenolysis occurs in all the
tissues in which glycogen is stored
Glycogenolysis

35. Glycogen is stored mainly in liver and
muscles
These two are the major sites of glyco-
genolysis

36. The purpose of hepatic glycogenolysis is to
maintain the blood glucose concentration
When blood glucose level decreases, glyco-
genolysis occurs in liver
Glucose is released into circulation, and
blood glucose level is restored

37. Glycogen cannot be converted into free
glucose in muscles
In muscles, glycogenolysis occurs mainly
to provide energy for muscle contraction

38. The key enzyme of glycogenolysis is
phosphorylase (glycogen phosphorylase)
It catalyses phosphorolytic removal of glucose
from glycogen as glucose-1-phosphate
This enzyme hydrolyses the terminal a-1,4-
glycosidic bonds

39. (Glucose)n + Pi
(Glucose)n‒1 + Glucose-1-phosphate
↓Phosphorylase

40. Large number of branches in the glycogen
molecule facilitate rapid glycogenolysis
Terminal glucose units on all the branches
can be split off simultaneously
Energy present in the glycosidic bond is
conserved by incorporating a phosphate
group into the liberated glucose molecule

41. The stepwise removal of glucose units from
each branch continues until only four glucose
units are left distal to a branch point
The molecule so formed is known as limit
dextrin

42. After the formation of limit dextrin, oligo-
(a-1,4  a–1,4) - glucan transferase acts
It transfers a trisaccharide unit from one
branch to another
Now, one branch has now got seven glucose
units distal to the branch point
The other has only one glucose unit linked to
the main chain by a-1,6-glycosidic bond

44. Now, the single glucose unit attached to the
chain by 1,6-glycosidic linkage is split off
This reaction is catalysed by amylo-1,6-
glucosidase (debranching enzyme)
This is not a phosphorolytic removal
The glucose unit is liberated as free glucose

46. The process of hydrolysis of 1,4- and 1,6-
glycosidic bonds continues
It ends only when a very small glycogen
molecule is left
This small molecule is used as glyocogen
primer for the next round of glycogenesis

47. The products of glycogenolysis are
glucose-1-phosphate and free glucose
These are formed in approximately 10:1
ratio
This is because branching occurs roughly
after every 10 glucose units

48. Glucose-1-phosphate is converted into
glucose-6-posphate by phosphoglucomutase
This reaction is reversible
Most tissues possess glucose-6-phosphatase
This splits off inorganic phosphate from
glucose-6-phosphate to liberate free glucose

50. Thus, the end product of glycogenolysis is
glucose in most of the tissues
An exception is muscle which lacks
glucose-6-phosphatase
In muscle, the end product is glucose-6-
phosphate

51. Glycogenolysis occurs in muscles when
energy is required for muscle contraction
Glucose-6-phosphate directly enters the
glycolytic pathway
The product is lactate if the conditions are
anaerobic

52. The regulatory enzyme is phosphorylase
It is regulated by covalent modification
The covalent modification is addition or
removal of phosphate
Regulation

53. Phosphorylase can exist in two forms:
Phosphorylase a (phospho-
phosphorylase)
Phosphorylase b
(dephospho-phosphorylase)
Phosphorylase a is the active form while
phosphorylase b is inactive

54. The liver and muscle enzymes are slightly
different from each other
In muscle, phosphorylase is a dimer, made
up of two identical subunits
Each subunit contains one molecule of
pyridoxal phosphate
Each subunit has got a serine residue which
can be phosphorylated

55. Phosphorylase b is a dimer in which the
serine residues are not phosphorylated
Phosphorylase b can be phosphorylated to
phosphorylase a by phosphorylase kinase
Phosphorylase kinase contains four types
of subunits – a, b, g and d

57. Phosphorylase kinase can exist in an
inactive form and an active form
The inactive form is phosphorylase kinase
b; active form is phosphorylase kinase a
In the b form, the a and b subunits are not
phosphorylated, and d subunits lack Ca+2

59. Phosphorylase kinase becomes fully
active when a and b subunits are
phosphorylated
Phosphorylation is catalysed by protein
kinase A

61. Protein kinase A becomes active when
cAMP concentration increases
cAMP concentration is increased by epi-
nephrine in muscles and by glucagon in
liver
The concentration is decreased by insulin
in both muscles and liver

63. Active phosphorylase kinase phospho-
rylates phosphorylase b
This converts inactive phosphorylase b
into active phosphorylase a
Phosphorylase a is dephosphorylated to
phosphorylase b by protein phosphatase-1

64. Protein kinase A also activates inhibitor-1 by
phosphorylating it
Inhibitor-1 inhibits protein phosphatase-1
This decreases the conversion of phospho-
rylase a into phosphorylase b

66. Thus, epinephrine and glucagon activate
phosphorylase
This increases the rate of glycogenolysis
Insulin has an opposite effect
It causes inactivation of phosphorylase
and decreases glycogenolysis

67. Regulation of glycogenesis
and glycogenolysis is:
Synchronous
Reciprocal