Transcript Glycogen Metabolism by Dr Tarek File

Qassim University
College of Medicine
Glycogen Metabolism
Dr. Tarek A Salem
Biochemistry
Objectives
• List the steps of glycogen biosynthesis (glycogenesis)
• Mention site of occurrence, regulation and importance of
glycogenesis.
• Differentiate between liver and muscle glycogen
• List the steps of glycogenolysis
• Mention site of occurrence, regulation and importance of
glycogenolysis.
• Explain the biochemical basis of glycogen storage disorders
Liver Cell
Glycogen
• Glycogen is the main storage form of carbohydrates in
animals. It is present mainly in liver and muscle.
• In the liver, glycogen can compose up to 8% of the fresh
weight (100–120 g in an adult) soon after a meal. Only the
glycogen stored in the liver can be made accessible to other
organs.
• In the muscles , glycogen is found in a much lower
concentration (1% to 2% of the muscle mass), but the total
amount exceeds that in the liver .
Glycogen is a polymer of glucose residues linked by
 alpha(14) glycosidic bonds, mainly
 alpha(16) glycosidic bonds, at branch points.
- Glycogen branches contain about 8 -12 glucose
residues.
Glycogenesis
• It is the formation of glycogen in muscle
and liver
• Its site in the cytoplasm of every cells
mainly liver and muscle
Glycogen
synthesis
Steps
Glucokinase
1- Glucose
Phosphoglucomutase
G6P
G1P
Mg++
ATP
ADP
UDP-Glucose pyrophosphorylase
2- G-1-P
UDP-glucose
UTP
PPi
H2O
Pyrophosphatase
2Pi
Glycogen synthesis
1-Glycogen synthase enzyme in presence of preexisting glycogen primer (glycogenin).
2- Chain is lenthened, branching enzyme transfers a
part of the α-1:6 glycosidic link.
3- The branches grow up by further addition of 1:4
glucosyl units.
4- The key regulatory enzyme is glycogen synthase
which present in 2 forms:
- Active (dephosphorylated form)
- Inactive (phosphorylated form)
Glycogen synthase
It catalyzes transfer of the glucose moiety of UDPglucose to the hydroxyl at C4 of the terminal residue
of a glycogen chain to form an a(1 4) glycosidic
linkage:
Glycogen(n) + UDP-glucose  Glycogen(n +1) + UDP
Glycogenolysis
• It is the breakdown of glycogen into glucose in liver and
lactic acid in muscles.
Glycogen Phosphorylase catalyzes phosphorolytic cleavage of
the α(14) glycosidic linkages of glycogen, releasing glucose-1phosphate as reaction product.
Glycogen(n) + Pi  Glycogen (n–1) + glucose-1-phosphate
CH 2OH
H
O
H
OH
H
H
OH
OH
H
OPO32
glucose-1-phosphate
Glycogenolysis
• G-1-P is converted into G-6-P by the action of
phosphoglucomutase.
• In liver, G-6-P is hydrolysed by the action of
G-6-phosphatase
free glucose
• In muscle, G-6-P by glycolysis
lactic
acid because absence of G-6-phosphatase
Pyridoxal phosphate
(PLP), a derivative of
vitamin B6, serves as
prosthetic group for
Glycogen Phosphorylase.
H
O
O
P
O
O
C
H2
C
OH
O

N
H
CH3
pyridoxal phosphate (PLP)
Glycogenolysis
The key regulatory enzyme is glycogen breakdown which
present in 2 forms:
- Active (Phosphorylated form)
- Inactive (Dephosphorylated form)
= Debranching enzyme is hydrolytic enzyme acts on
α1 6 glycosidic link giving free glucose.
= Muscle glycogen is to provide muscle with glucose.
= Liver glycogen is to maintain blood glucose between meals.
= After 12 -18 hr fasting, liver glycogen whereas muscle
glycogen is after prolonged exercise.
Difference between muscle and liver glycogen
Liver glycogen
Muscle glycogen
Amount
Source
Hydrolysis
More in concentration
Glucose and other precursore
Give blood glucose
More in amount
Glucose only
Give lactic acid
Starvation
Muscular
exercise
Converted into blood glucose
Depleted
Not affected
Depleted
Effect of
Hormons
Insulin
Adrenaline
Thyroxine
Glucagon
Insulin
Adrenalin
Thyroxine
Glucagon
Regulation of glycogen metabolism
In Fasting:
Glucagon
• cAMP activates
Protein Kinase A
which phosphorylates
and inactivates
glycogen synthase
• Little glycogen synthesis
during fasting
Regulation of glycogen metabolism
In Fasting:
Glucagon
• cAMP activates
Protein Kinase A
which phosphorylates
and activates
glycogen
phosphorylase
• Fasting results in increased
glycogenolysis
Regulation of glycogen metabolism
• In Feeding:
Insulin
cAMP is reduceded
stimulates phosphodiesterase
induces and activates protein phosphatase-1
Activates
Glycogen Synthase (Glycogenesis is activated)
While Glycogen Phosphorylase is inactivated
(Glycogenolysis is inactivated)
• Feeding results in glycogen synthesis
Coordinated regulation of glycogen metabolism
Glycogen storage diseases (GSD)
• They are the result of defects in the processing of
glycogen synthesis or breakdown within muscles,
liver, and other cell types.
• GSD has two classes of cause: genetic and
acquired.
• Genetic GSD is caused by any inborn error of
metabolism.
• In livestock, acquired GSD is caused by
intoxication with the some alkaloids.
Types of GSD
• There are eleven distinct diseases that are
commonly considered to be glycogen storage
diseases.
• Although glycogen synthase deficiency does not
result in storage of extra glycogen in the liver, it is
often classified with the GSDs as type 0 because it
is another defect of glycogen storage and can
cause similar problems.)
glycogen
Glycogen Storage Diseases
are genetic enzyme
deficiencies associated with glucose-1-P
excessive glycogen
Glucose-6-Phosphatase
accumulation within cells.
glucose-6-P
Some enzymes whose
deficiency leads to
glycogen accumulation are
part of the inter-connected
pathways shown here.
glucose + Pi
fructose-6-P
Phosphofructokinase
fructose-1,6-bisP
Glycolysis continued
Symptoms in addition to excess glycogen storage:
 When a genetic defect affects mainly an isoform of an
enzyme expressed in liver, a common symptom is
hypoglycemia, relating to impaired mobilization of
glucose for release to the blood during fasting.
 When the defect is in muscle tissue, weakness &
difficulty with exercise result from inability to
increase glucose entry into Glycolysis during exercise.
 Additional symptoms depend on the particular
enzyme that is deficient.
Glycogen Storage Disease
Symptoms, in addition to
glycogen accumulation
Type I, liver deficiency of
Glucose-6-phosphatase (von
Gierke's disease)
hypoglycemia (low blood
glucose) when fasting, liver
enlargement.
Type IV, deficiency of
branching enzyme in various
organs, including liver
(Andersen's disease)
liver dysfunction and early
death.
Type V, muscle deficiency of
Glycogen Phosphorylase
(McArdle's disease)
muscle cramps with exercise.
Type VII, muscle deficiency of
Phosphofructokinase.
inability to exercise.