To understand :
Purpose of regulation of glycogen metabolism
Processes involved and
the reciprocal regulation of glycogenesis and
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General mechanisms involved in the
regulation of enzyme activities
Regulation of enzyme
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Key enzymes involved in the regulation of
Both these enzymes
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Substrate concentration and allosteric
Glycogen Synthase is
allosterically activated by
High blood glucose
concentration leads to elevated
When glycolytic pathway is
saturated, excess glucose-6-P
activates Glycogen synthase
and thus is stored as glycogen.
High Blood Glucose
Saturated Glycolytic pathway
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Covalent modification- General concepts
Reversible phosphorylation and dephosphorylation
Hormone mediated C-AMP mediated cascade
Phosphorylation is mediated by Protein kinase A
Dephosphorylation is carried out by Phosphatase
Insulin causes dephosphorylation by stimulating Phosphatase and
Phosphodiesterase (enzyme that breaks down cAMP)
Glucagon causes phosphorylation by stimulating Protein kinase A
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Regulation of glycogen synthase by
Glycogen synthase exists in both phosphorylated or
Active glycogen synthase a is dephosphorylated and
inactive glycogen synthase b is phosphorylated
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Covalent modification of glycogen
Phosphatase Protein kinase A
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Mechanism of Phosphorylation of
The cAMP cascade results in
phosphorylation of a serine
hydroxyl of Glycogen
synthase, which promotes
transition to the inactive
C AMP cascade is active
during fasting or starvation
and is activated by glucagon
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Implications of Phosphorylation
Phosphorylation of Glycogen Synthase promotes the "b" (less active)
The cAMP cascade thus inhibits glycogen synthesis.
Instead of being converted to glycogen, glucose-1-P in liver may be converted
to glucose-6-P, and dephosphorylated for release to the blood.
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Role of Insulin in Glycogenesis
Insulin promotes Glycogenesis.
Insulin, produced in response to high blood glucose causes activation of
Phosphoprotein Phosphatase resulting in removal of regulatory phosphate
residues from Glycogen Synthase enzyme converting it to
In liver insulin increases the activity of phosphodiesterase, promoting
hydrolysis of c AMP terminating hormone action.
Insulin thus antagonizes effects of the cAMP cascade induced by glucagon &
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C AMP 5’AMP
cAMP Cascade and the role of hormones
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Regulation of Glycogenolysis
Glycogen Synthase and Glycogen Phosphorylase are reciprocally regulated, by
allosteric effectors and by phosphorylation.
The control of phosphorylase differs between liver & muscle
In the liver the role of glycogen is to provide free glucose for export to
maintain the blood concentration of glucose;
In muscle the role of glycogen is to provide a source of glucose 6-phosphate
for glycolysis in response to the need for ATP for muscle contraction.
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Regulation of Muscle Phosphorylase by
Liver phosphorylase is
less sensitive to these
inhibited by excess
product of the
On the contrary,
is stimulated by
the substrate of
inhibited when ATP
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Regulation of Glycogenolysis by Covalent
The cAMP cascade results in phosphorylation of a serine hydroxyl of Glycogen
Phosphorylase, which promotes transition to the active state.
The phosphorylated enzyme is less sensitive to allosteric inhibitors.
Thus, even if cellular ATP and glucose-6-phosphate are high, Phosphorylase will be
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Phosphorylation of Phosphorylase
The enzyme phosphorylase is activated by phosphorylation catalyzed by
phosphorylase kinase (to yield phosphorylase a) and
Inactivated by dephosphorylation catalyzed by phosphoprotein phosphatase
(to yield phosphorylase b), in response to hormonal and other signals.
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Role of cAMP In Glycogen degradation
Increasing the concentration of cAMP activates cAMP-dependent protein
kinase, which catalyzes the phosphorylation by ATP of inactive phosphorylase
kinase b to active phosphorylase kinase a, which in turn, phosphorylates
phosphorylase b to phosphorylase a.
In the liver, cAMP is formed in response to glucagon, which is secreted in
response to falling blood glucose; muscle is insensitive to glucagon.
In muscle, the signal for increased cAMP formation is the action of
norepinephrine, which is secreted in response to fear or fright, when there is a
need for increased glycogenolysis to permit rapid muscle activity.
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C AMP 5’AMP
cAMP Cascade and the role of hormones
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Role of Ca++ in glycogen degradation
Ca++ also regulates glycogen breakdown in muscle.
During activation of contraction in skeletal muscle, Ca++ is released from the
sarcoplasmic reticulum to promote actin/myosin interactions.
The released Ca++ also activates Phosphorylase Kinase, which in muscle
includes calmodulin as its δ subunit.
Phosphorylase Kinase is partly activated by binding of Ca++ to this subunit.
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Role of calcium in muscle degradation
Phosphorylase Kinase is partly
activated by binding of Ca++ to
Further activation is brought by
Phosphorylase kinase- Ca++
Phosphorylase kinase- Ca++
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Role of calcium in the activation of
Muscle phosphorylase kinase, which activates glycogen phosphorylase, is a tetramer of four
different subunits-α, β ,Υ and δ .
The α and β subunits contain serine residues that are phosphorylated by cAMP-dependent protein
kinase. The δ subunit is identical to the Ca2+-binding protein calmodulin.
The binding of Ca2+ activates the catalytic site of the subunit even while the enzyme is in the
dephosphorylated b state; the phosphorylated a form is only fully activated in the presence of Ca2+.
α β δ γ
Protein kinase A
Ca ++P P
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Role of Insulin in Glycogen degradation
Both phosphorylase and phosphorylase kinase are dephosphorylated and
inactivated by protein phosphatase.
Protein phosphatase is stimulated by Insulin,
Therefore Insulin by inhibiting the activation of these enzymes inhibits the
overall process of glycogenolysis.
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Reciprocal regulation of Glycogenesis
Glycogen Synthase & Phosphorylase activity are reciprocally regulated
At the same time as phosphorylase is activated by a rise in concentration of
cAMP (via phosphorylase kinase), glycogen synthase is converted to the inactive
Thus, inhibition of glycogenolysis enhances net glycogenesis, and inhibition of
glycogenesis enhances net glycogenolysis
Both processes do not occur at the same time.
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When the blood glucose is low as in fasting or starvation, the predominant
hormones such as Glucagon and epinephrine trigger the C- AMP mediated
In the phosphorylated state glycogen synthase becomes inactive whereas
Phosphorylase becomes active,
Glycogenesis is switched “off” and Glycogenolysis is switched “on”.
Liver glycogen breakdown restores the lowered blood glucose concentration
back to normal
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When the blood glucose concentration is high- Insulin, the main hormone,
promotes the dephosphorylated forms of the enzymes by disrupting the c AMP
mediated phosphorylation cascade and by stimulating the phosphatase activities.
Phosphorylase in the dephosphorylated form becomes inactive whereas the
Glycogen synthase in that state becomes active.
Hence extra glucose is used for glycogen synthesis and blood glucose
concentration is restored back to normal.
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Glycogenesis and glycogenolysis are reciprocally regulated.
Insulin promotes glycogenesis.
Glucagon and epinephrine promote glycogenolysis.
Glycogenesis is the process of well-fed state.
Glycogenolysis is the process of Fasting or starvation.
Both these processes are meant for maintaining the blood glucose
concentration within the normal range.
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