GLYCOGEN
METABOLISM
Dr. Phari Dajangju
JNMC, AMU
Introduction
Storage form of Glucose
Polymer held by glycosidic linkages
Stored in Liver and Muscles
Source of fuel for brain
Structure
In cytoplasm as granules
inner linear chain
Outer branched
Central Glycogenin protein
Function
Storage form
Energy for brain
Reserve fuel for muscle contraction
GLYCOGENOLYSIS
Enzymes of Glycogenolysis
Phosphorylase
Glucose-6Phosphatase
BifunctionalDebranching
enzyme
Phosphoglucomutase
Step 1:Depolymerization
(Release of Glu-1-P)
Enzyme:Phosphorylase
Co Enzyme:Pyridoxal phosphate
Orthophosphate splits between C1 and C4 of adjacent
glucose
Stops 4 units before branching point
Step 2: Remodelling &
Debranching
Bifunctional enzyme
Transferase
Alpha-1,6-glucosidase
Release of free glucose residue
Linear Glycogen
Step 3:Conversion of
Glu-1-P to Glu-6-P
Enzyme: Phosphoglucomutase
The active site of Mutase has phosphorylated
serine
Glu-1,6-bisP intermediate formed
Step 4: Fate of Glu-6-P
Reaction catalysed by
Phosphotase
Regulation of
Glycogenolysis
Regulation of enzyme Glycogen Phosphorylase
Hormonal action of Glucagon/Epinephrine
Mechanism is similar in Liver and Muscle
Epinephrine in Muscle
Glycogen
Phosphorylase
2 Isozyme Glycogen Phosphorylase a and b
Each exists in R and T state
Dimer with Serine residue
Phosphorylase kinase promotes Phosphorylase
b—>a
Phosphorylase kinase
Structure4 subunits, 4 of each
Activation1.Phosphorylation of beta -partial activation
2.Calcium attaches to delta-full activation
Regulation of glucose
breakdown in muscles
Low energy state1.Epinephrine through Phosphorylase kinase
Phosphorylase b—->a
2.AMP from degradation of ATP as allosteric
activator of Phosphorylase b from T—>R state
Resting state1.ATP shift Phophorylase b R—>T state
2.High Glu-6-P favour T state
Regulation of glycogen
breakdown in Liver
Liver Phosphorylase sensitive to free Glu
Free Glu binds to active site, causes covalent
modification R—>T state
Low Glu..activate Phosphorylase a
Insulin promotes uptake of Glu and
phosphorylation to Glu-6-P
Glucagon signal
pathway
Alpha cells of pancreas secrete Glucagon
Epinephrine by adrenal medulla
Epinephrine bind to alpha adrenergic receptor
Similar cascade of reactions
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.
14-Jan-17
NAMRATA CHHABRA, M.D.
GLYCOGENESIS
GLYCOGENESIS
Mainly in Liver and Muscles
Liver Glycogen functions as storage and export of
glucose for maintaining level
Muscle glycogen as readily available source of glucose
Phases of Glycogenesis
Activation
Initiation
Glycogen
Branching
Elongation
ACTIVATION OF
GLUCOSE
Step 1:Phosphorylation of Glucose
Step 2:Conversion of Gluc-6-P to
Gluc-1-P
Step-3- Conversion of Glucose-1-P
to UDP-Glucose
Enzyme UDP Glu Pyrophosphorylase
INITIATION
Initiation
Glycosidic bond between the C1 of the glucose moiety of UDPglucose and the hydroxyl oxygen of a tyrosine side-chain of
Glycogenin.
Glucosyl Transferase
UDP is released as a product.
Each subunit of glycogenin catalyzes the addition of eight glucose
units to its partner in the glycogenin dimer.
At this point, glycogen synthase takes over to extend the glycogen
molecule.
Elongation
Catalyzed by Glycogen Synthase
New glucosyl units added to nonreducing terminal
residues of glycogen.
Formation of α-1,4-glycosidic linkage.
.
Incorporation of UDP-Glucose intoglycogen
Glycogen Branching
Amylo-(1,4)—>(1,6)-transglucosidase
Increases the solubility
Increases terminal residue which are sites for
action of Synthase and Phosphorylase
Regulation of glycogen
synthesis
Glycogen Synthase
GS 1 in muscles, GS2 in Liver
Phosphorylation inactivates a-->b
Glu-6-P is allosteric effector
Role of Insulin in Glycogenesis
Promotes Glycogenesis
Causes activation of Phosphoprotein Phosphatase
resulting dephosphorylation of Glycogen Synthase
In liver insulin increases the activity of
phosphodiesterase, promoting hydrolysis of cAMP
Insulin thus antagonizes effects of the cAMP
cascade induced by glucagon & epinephrine.
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NAMRATA CHHABRA, M.D.
REGULATION
General mechanisms involved in the
regulation of enzyme activities
Regulation of
enzyme activity
Induction/Repres
sion
Covalent
modification
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Allosteric
modification
NAMRATA CHHABRA, M.D.
Substrate/produ
ct concentration
Key enzymes involved in the regulation
of glycogen metabolism
Glycogen synthaseFor Glycogenesis
Glycogen
Phosphorylase
NAMRATA CHHABRA, M.D.
Both these
enzymes are
reciprocally
regulated.
Reciprocal regulation of Enzymes
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.
14-Jan-17
NAMRATA CHHABRA, M.D.
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
14-Jan-17
NAMRATA CHHABRA, M.D.
Covalent modification- General
concepts
Reversible phosphorylation and dephosphorylation
Hormone mediated cAMP 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)
NAMRATA CHHABRA,
M.D.
Glucagon14-Jan-17
causes phosphorylation
by stimulating
Protein kinase A
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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NAMRATA CHHABRA, M.D.
Covalent modification of glycogen
synthase
Glycogen synthase
a
Pi
Phosphatase
H2O
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Active
p
Glycogen synthase
b
Inactive
NAMRATA CHHABRA, M.D.
ATP
Protein
kinase A
ADP
Regulation of Glycogenolysis by
Covalent Modification
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.
14-Jan-17
NAMRATA CHHABRA, M.D.
Role of cAMP In Glycogen degradation
cAMP activates cAMP dependent Protein Kinase
Phosphorylation of inactive phosphorylase kinase b to a
Phosphorylation of inactive Glycogen Phosphorylase b to a
In the liver, cAMP is formed in response to glucagon, muscle is
insensitive to glucagon.
In muscle, increased cAMP formation is the action of
norepinephrine
14-Jan-17
NAMRATA CHHABRA, M.D.
Role of calcium in muscle degradation
Phosphorylase Kinase is partly
activated by binding of Ca++
Phosphorylase Kinase
Dephosphorylated (inactive)
Ca++
Further activation is brought by
phosphorylation.
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NAMRATA CHHABRA, M.D.
Phosphorylase kinase- Ca++
Partly active
ATP
Phosphorylase kinase- Ca++
Phosphorylated- active
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