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To understand how glycogen is synthesized
and degraded in liver and muscle.
To understand how hormones like adrenalin
and glucagon affect glycogen synthesis and
Glycogen is the major storage form of carbohydrate
in animals and corresponds to starch in plants.
Occurs mainly in liver and muscle.
Biomedical ImportanceBiomedical Importance
Muscle glycogen acts as a convenient source of
hexose units for glycolysis within muscle itself. Only
depleted significantly after prolonged vigorous
Liver glycogen is largely concerned with storage and
export of hexose units for maintenance of blood
glucose, particularly between meals. After 12-18h of
fasting, the liver becomes nearly depleted of
Glycogen storage diseases are a group of inherited
disorders characterized by deficient mobilization of
glycogen or deposition of abnormal forms of
Glycogenesis- glycogen synthesisGlycogenesis- glycogen synthesis
Occurs mainly in muscle and liver.
Glucose is phosphorylated to glucose 6-phosphate as in
the first step of glycolysis.
Glucose-6-phosphate is converted to glucose-1-
phosphate by phosphoglucomutase. In this reaction, the
enzyme itself becomes phosphorylated and glucose 1,6-
bisphosphate is an intermediate.
Glucose 6-phosphate Glucose 1-phosphate
The key reaction in glycogen synthesis is the formation
of UDP-glucose by the action of UDP-glucose
Glucose 1-phosphate + UTP→ UDP-glucose + PPi
This reaction proceeds to the right because PPi is rapidly
hydrolyzed to inorganic phosphate.
UDP-glucose is the immediate donor of glucose residues
in the reaction catalyzed by glycogen synthase, which
promotes the transfer of the glucose residue of UDP-
glucose to a non-reducing end of a branched glycogen
molecule (primer must have at least 8 glucose residues)
Glycogen synthase cannot make the (α1→6) bonds
found at branch points of glycogen. This is done by
the glycogen-branching enzyme “amylo (1→4) to
(1→6) transglycosylase.” Branching makes glycogen
more soluble and provides more non-reducing ends
which act as sites for glycogen synthase and glycogen
Initiation of a glycogen particleInitiation of a glycogen particle
Because glycogen synthase
requires a primer, a new
glycogen particle is formed
by the protein glycogenin
glycosylated on a specific
tyrosine residue by UDP-
glucose. Further glucose
molecules are attached in
the 1→ 4 position to make a
short glucose chain which
can then act as a primer for
Glycogenolysis- glycogen breakdownGlycogenolysis- glycogen breakdown
Glycogen can enter the glycolytic pathway as glucose 6-
phosphate following the action of two enzymes: glycogen
phosphorylase and phosphoglucomutase.
Glycogen phosphorylase releases terminal glucose
residues from the non-reducing end of glycogen chains
breakdown near abreakdown near a
branch pointbranch point
This requires a
“debranching enzyme” -
which has a transferase and
a glucosidase activity
Glucose 1-phosphate, the end product of the
glycogen phosphorylase reaction, is converted to
glucose 6-phosphate by phosphoglucomutase:
glucose 1-phosphate glucose 6-phosphate
In liver (and kidney), but not in muscle, there is a
specific enzyme, glucose 6-phosphatase, that
removes phosphate from glucose 6-phosphate.
The glucose formed can diffuse from the cell into
Cyclic AMP integrates the regulation ofCyclic AMP integrates the regulation of
glycogenolysis and glycogenesisglycogenolysis and glycogenesis
The principle enzymes controlling glycogen metabolism are
glycogen phosphorylase and glycogen synthase.
These enzymes are regulated by a complex series of reactions
involving both allosteric mechanisms and covalent modification by
*Glycogen phosphorylase is activated by phosphorylation
*Glycogen synthase is inactivated by phosphorylation
Cyclic AMP activates muscleCyclic AMP activates muscle
Epinephrine (adrenaline) activates the β-adrenergic receptor on the
surface of muscle cells
This activates, via trimeric G proteins, the enzyme adenylate cyclase,
which makes cyclic AMP from ATP
Cyclic AMP, or cAMP, activates cAMP-dependent protein kinase (PKA)
R2C2 (inactive) + 4cAMP R2-(AMP)4 + 2C (active)
Active PKA phosphorylates and activates phosphorylase b kinase
Active phosphorylase b kinase phosphorylates and activates
phosphorylase b, which can now mobilize glycogen
Activation of phosphorylase kinase inActivation of phosphorylase kinase in
Phosphorylase kinase is also activated by
Subunit structure (αβγδ)2
α,β - phosphorylated by PKA
γ - catalytic subunit
δ - calmodulin
Calmodulin binds Ca2+
Binding of Ca2+
by δ subunit enhances activity
of phosphorylase kinase
synchronizes the activation of
phosphorylase with muscle contraction
Control of phosphorylase in muscle. The sequence of
reactions arranged as a cascade allows amplification of the
hormonal signal at each step (n= number of glucose
residues; G6P, glucose 6-phosphate).
Glycogen SynthaseGlycogen Synthase
Glycogen synthase is also regulated by reversible
phosphorylation, but in this case, the phosphorylated
enzyme is inactive.
*Glycogen synthase a - active form- dephosphorylated
*Glycogen synthase b - inacitve form- phosphorylated
In muscle, when PKA is active and glycogenolysis is
promoted, glycogen synthase is maintained inactive by
the same pathway
1. Glycogen represents the principal storage form of
carbohydrate in the mammalian body, present mainly
in the liver and muscle.
2. In the liver, its major function is to service the other
tissues via formation of blood glucose. In muscle, it
serves the needs of that organ only, as a ready
source of metabolic fuel.
3. Glycogen is synthesized from glucose and other
precursors by the pathway of glycogenesis. It is
broken down by a separate pathway known as
glycogenolysis. Glucose is not exported from
muscle due to absence of glucose 6-phosphatase.
4. 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
5. Inherited deficiencies in specific enzymes of
glycogen metabolism in both liver and muscle are
the causes of glycogen storage diseases.