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GLYCOGENOLYSIS
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Outline:
Definition
Steps of glycogenolysis
Diagrammatic representation of
glycogenolysis
Regulation of glycogenolysis
Clinical implification
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DEFINITION:
Breakdown of glycogen to
glucose is called glycogenolysis.
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STEPS OF
GLYCOGENOLYSIS:
First step: The overall reaction for the first
step
Glycogen + Pi glycogen +(n residues) (n-1 residues)
glucose-1-phosphate
Enzyme used for this step is glycogenPhosphorylase which uses vit. B6 derivative
as co-factor.
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Glycogen Phosphorylase breaks down glucose
polymer at alpha-1,4 linkages until 4 glucose
residues left on a branch called limit dextrin.
Second step: Enzyme alpha-1,4 alpha-1,4
glucan transferase transfer trisaccharide from one
side to other exposing alpha,1-6 branch point.
Third step: Hydrolytic splitting of alpha-1,6
glucosidic linkage by debranching enzyme and
one molecule of free glucose is produced.
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Fourth step:
Glucose-1-phosphate is
converted to glucose-6-phosphate by
the enzyme phophoglucomutase.
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Steps of glycogenolysis
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STRUCTURE OF GLYCOGEN PHOSPHORYLASE
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glucose-1-phosphate
phosphoglucomutase
glucose-6-phosphate
free glucose glycolysis(in kidney and liver) (in muscles)
energy
Glucose-6-phosphatase
blood
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REGULATION OF GLYCOGENOLYSIS
Cyclic AMP dependant protein kinase has
dual effects on glycogenolysis regulation
> activation of Phosphorylase enzyme
> activation of inhibitor-1
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> Activation of Phosphorylase
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> Activation of inhibitor-1
Inhibitor-1 (inactive)
protein kinase Pi
inhibitor-1-p (active)
This inhibits protein phosphatase-1 which
inhibits the inactivation of Phosphorylase
kinase. As a result more and more
Phosphorylase is converted to active form
ACTIVATION AND INACTIVATION OF MUSCLE
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ACTIVATION AND INACTIVATION OF MUSCLEPHOSPHORYLASE:
> phosphorylase(active)+4H2O
Phosphorylase rupturing enzyme
phosphorylase(inactive)+4Pi
phosphorylase(inactive)+4ATP
Phosphorylase kinase
Mg ion
phosphorylase(active)+4ADP
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ROLE OF Ca IONS:
Glycogenolysis increase in muscle
contraction immediately after onset of
contraction. This involves rapid activation of
Phosphorylase due to activation of protein
kinase by Ca ions, the same signal that
initiates contraction.
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Muscle phosphorylase has 4 types of subunits: alpha, beta, gamma, delta
alpha and beta has serine residueswhich are phosphorylated by cyclic-AMPdependant protein kinase
beta subunit binds 4 Ca ions and isidentical to calmodulin
binding of Ca ions activatescatalytic site of gamma subunit while themolecule remains in dephosphorylatedconfiguration
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A second molecule of calmodulin can interact
with phosphorylase kinase causing further activation
So muscle contraction andglycogenolysis are carried out by
same Ca binding protein.
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CLINICAL APPLICATION:
GLYCOGEN STORAGE DISEASESGSDs
These are a group of inherited disordersassociated with glycogen metabolism and is
characterized by deposition of normal or abnormal type and large quantity of glycogen intissues.
GSDs also known as glycogenosis.
THE MOST IMPORTANT GSD IS
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VON GIERKE’S DISEASE:
DEFICIENT ENZYME:
glucose-6- phosphatase
INHERITANCE:autosomal recessive
SIGN AND SYMPTOMS:
1) Hypoglycemia as very little glucose isderived from liver
2) Fats are used as energy source leading to
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2) Fats are used as energy source leading to
ketosis and acidemia.
3) Increase acetyl-CoA causes increase incholesterol level which produces xanthomas.
4) Persistent hypoglycemia has two effects:> decrease insulin secretion which decreases
protein synthesis resulting stunted growth(dwarfism)
> increase secretion of catecholamine causemuscle glycogen to breakdown producing lacticacid causing lactic acidosis
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5) Increase blood lactic acid competes with
urate excretion by kidney leading to increaseblood uric acid level. There is also evidence
that there is increased uric acid synthesis in
these children which accumulate in jointsresulting in GOUT
Other GSDs are described in table below:
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.
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.
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TYPE NAME ENZYMEEFI
CIENCY
CLINICAL FEATURES
II Pompe’s disease Lysosomal
glucosidase
Glycogen accumulate in
lysosomes, death from hearth
failure by age 2, muscle
dystrophy
III Cori’s disease/
Limit
dextrinosis
Debranching
enzyme
Fasting hypoglycemia,
hepatomegaly in infancy
IV Anderson’s
disease/
amylopectinosis
Branching
enzyme
Hepatosplenomegaly, death from
heart or liver failure in first
year of life
V McArdle’s
syndrome
Muscle
Phosphorylase
Poor exercise tolerance, blood
lactate low after exercise.
VI Her’s disease Liver
Phosphorylase
Hepatomegaly, glycogen
accumulate in liver, mild
hypoglycemia
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Many other GSDs like type VII, VIII, IX
and X but most common are these six GSDs
REFERENCES:
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REFERENCES:
1) Murray, Granner, Rodwell, “Harper’s Illustrated
Biochemistry” 27th
edition Ch:19 Page: 159-166
2) MNChatterjea, Rana Shinde, “Textbook Of
Medical Biochemistry” 7th edition Ch:23 part II
Page: 327-333
3) Lubert Styrer, Tymoczha, Berg,
“W.H.Freemann and Company Biochemistry”
5
th
edition Ch:21 Page:866-8764) wikipedia
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ACKNOWLEDGMENTS:1) To Supreme Power ALLAH AL-MIGHTY
2) Head Of Biochemistry DepartmentProf. Dr. Khawaja Fayyaz
3) Mr. Jamshad Iqbal
4) Dr. Safqat Nazir
5) Dr. Huda6) Dr. Sarfaraz
7) Dr. Javaria
8) My Parents
9) Library staff
10) My Seniors of 3rd year
11) Class fellows Safeet, Umair
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