Reciprocal regulation of glycogenesis and glycogenolysis

1. Regulation of Glycogen metabolism
NAMRATA CHHABRA, M.D., BIOCHEMISTRY
Glycogen metabolism-Part-3
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2. Learning objectives
To understand :
Purpose of regulation of glycogen metabolism
Processes involved and
the reciprocal regulation of glycogenesis and
glycogenolysis
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3. General mechanisms involved in the
regulation of enzyme activities
Regulation of enzyme
activity
Covalent
modification
Allosteric
modification
Substrate/product
concentration
Induction/Repression
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4. Key enzymes involved in the regulation of
glycogen metabolism
Glycogen synthase-
For Glycogenesis
Glycogen
Phosphorylase
Both these enzymes
are reciprocally
regulated.
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5. Substrate concentration and allosteric
modification
Substrate- Glucose-6-P
 Glycogen Synthase is
allosterically activated by
glucose-6-P.
 High blood glucose
concentration leads to elevated
intracellular glucose-6-P.
When glycolytic pathway is
saturated, excess glucose-6-P
activates Glycogen synthase
and thus is stored as glycogen.
High Blood Glucose
High Glucose-6-P
Saturated Glycolytic pathway
Glycogen
Synthase
v
Glycogenesis
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6. 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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7. Regulation of glycogen synthase by
covalent modification
Glycogen synthase exists in both phosphorylated or
dephosphorylated states
Active glycogen synthase a is dephosphorylated and
inactive glycogen synthase b is phosphorylated
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8. Covalent modification of glycogen
synthase
Glycogen
synthase
a
Glycogen
synthase
b
Phosphatase Protein kinase A
ATPPi
H2O ADP
Active
Inactive
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p

9. Mechanism of Phosphorylation of
glycogen synthase
 The cAMP cascade results in
phosphorylation of a serine
hydroxyl of Glycogen
synthase, which promotes
transition to the inactive
state.
 C AMP cascade is active
during fasting or starvation
and is activated by glucagon
or epinephrine.
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10. Implications of Phosphorylation
Phosphorylation of Glycogen Synthase promotes the "b" (less active)
conformation.
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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11. 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
dephosphorylated/active form.
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 &
epinephrine.
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12. ATP
Glycogen
synthase a
Glycogen
synthase b
C AMP 5’AMP
Adenylate cyclase
Protein
Phosphatase
Phosphodiesterase
ATP ADP
Protein
Kinase A
H2OPi
IG
G
I
IG InsulinGlucagon
Glucagon favors
phosphorylation
thus inhibits
glycogenesis
Insulin favors
dephosphorylation thus
stimulates Glycogenesis
cAMP Cascade and the role of hormones
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13. 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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14. Regulation of Muscle Phosphorylase by
allosteric modification
Phosphorylase
Negative
effectors
ATP Glucose-6-P
Positive
effectors
AMP
Liver phosphorylase is
less sensitive to these
allosteric modifier.
Phosphorylase is
inhibited by excess
Glucose-P, the
product of the
reaction sequence.
On the contrary,
Glycogen synthase
is stimulated by
excess Glucose-6-P,
the substrate of
this pathway.
Glycogen
breakdown is
inhibited when ATP
and glucose-6-
phosphate are
plentiful.
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15. Regulation of Glycogenolysis by Covalent
Modification (phosphorylation):
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
active.
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16. 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.
C AMP
Phosphorylase
Kinase
(Active)
Protein Kinase
A
Phosphorylase
(Active)
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17. 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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18. ATP
Phosphorylase
kinase
(Inactive)
Phosphorylase
(Inactive)
C AMP 5’AMP
Adenylate cyclase
Protein
Phosphatase
Phosphodiesterase
ATP ADP
Protein
Kinase A
H2OPi
IG
G
I
IG
Insulin
Glucagon
Glucagon favors
phosphorylation
thus promotes
Glycogenolysis
Insulin favors
dephosphorylation
thus inhibits
Glycogenolysis
cAMP Cascade and the role of hormones
Phosphorylase
(Active)
Phosphorylase
kinase
(Active)
ATP
ADP
Phosphatase
H2O
Pi
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19. 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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20. Role of calcium in muscle degradation
Phosphorylase Kinase is partly
activated by binding of Ca++ to
this subunit.
Further activation is brought by
phosphorylation.
Phosphorylase Kinase
Dephosphorylated (inactive)
Phosphorylase kinase- Ca++
Partly active
Phosphorylase kinase- Ca++
Phosphorylated- active
Ca++
ATP
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21. Role of calcium in the activation of
phosphorylation kinase
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+.
Phosphorylase
Kinase
α γδβ
Phosphorylase
Kinase
α β δ γ
Protein kinase A
Ca++
Phosphatase
Ca ++P P
Active Enzyme
Inactive Enzyme
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22. 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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23. Reciprocal regulation of Glycogenesis
and glycogenolysis
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
form.
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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24. Biological significance
When the blood glucose is low as in fasting or starvation, the predominant
hormones such as Glucagon and epinephrine trigger the C- AMP mediated
phosphorylation cascade.
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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25. Biological significance
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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26. Conclusion
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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27. Thank you
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