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GLYCOGEN METABOLISM
• Glycogen is the major storage carbohydrate in
animals; it’s a branched polymer of α-D-glucose
• It occurs mainly in liver and muscle

• Because of its greater mass, muscle contains about
three to four times as much glycogen as the liver
• Muscle glycogen is a readily available source of
glucose for glycolysis within the muscle itself
1

• Liver glycogen functions to store and export glucose to
maintain blood glucose between meals
• Glycogen is present in the cytosol in the form of
granules which contain regulatory proteins as well as
enzymes that catalyze the synthesis and degradation of
glycogen
-After 12-18 hours of fasting the liver glycogen is
almost totally depleted
• Glycogen storage diseases are inherited disorders
characterized by deficient mobilization of glycogen or
deposition of abnormal forms leading to muscular
weakness or death
2

Pathways of glycogenesis and of glycogenolysis in the liver
Glycogen
(1
4 and 1
glucosyl units)

UDP

6

Pi

Branching enzyme
(1

4 Glucosyl units)x

Insulin

–

Glycogen
primer

Glycogen
synthase

Uridine diphosphate
glucose (UDPGlc)

–

cAMP

+

+

Glycogen
Phosphorylase

Glucagon
Epinephrine

Glucantransferase
Debranching enzyme

UDPglc pyrophosphorylase

Free
glucose
from
debranching
enzyme

PPi
Uridine triphosphate
(UTP)

Glucose 1-P
Glucose 6-P

Glucose 6 phosphatase

To glycolysis and pentose
phosphate pathway
Glucokinase

Glucose
3

Glycogenesis occurs mainly in muscle and liver

• As in glycolysis glucose is phosphorylated to glucose 6-P
by hexokinase in muscle and glucokinase in liver
• Glucose 6-phosphate is isomerized to glucose 1-phosphate
by phosphoglucomutase
• Next glucose 1-phosphate reacts with uridine triphosphate
(UTP) to form an active nucleotide, uridine diphosphate
glucose (UDPGlc) and pyrophosphate, catalyzed by UDPGlucose pyrophosphorylase
...

- Glycogenin autocatalyzes the addition of
eight glucose units; UDPGlc is the donor in
this autoglycosylation
...
Inhibits glycogenesis
- Insulin also promotes glycogenesis in muscle by raising
glucose 6-phosphate concentration which stimulates
dephosphorylation and activation of glycogen synthase
- dephosphorylation of glycogen synthase b is carried out
by protein phosphatase-1
8

• Glycogen synthase catalyzes only the synthesis of α-1,4
linkages
• Another enzyme is required to form the α-1,6 linkages
that make glycogen a branched polymer
• Branching involves attachment of existing glycogen
chain
- Addition of glucose residue to a pre-existing glycogen
molecule occurs at the non-reducing end so the
elongation occurs as successive 1→4 linkages
- When the chain has lengthened by at least 11 glucose
residues, branching enzyme transfers a part of 1→4
chain (at least 6 glucose residues) to a neighbouring
9
chain to form a 1→6 linkage
...
Thus
branching increases the rate of glycogen synthesis and
degradation
10

Glycogenolysis is a separate pathway (not reversal of
glycogenesis)
-Glycogen phosphorylase catalyzes the rate-limiting step
in glycogenolysis by promoting phosphorylitic cleavage
by inorganic phosphate (phosphorolysis) of the 1→4
linkages of glycogen to yield glucose 1-phosphate
-The terminal glucosyl residues from the outer most
chains of glycogen are removed sequentially until
approximately four glucose residues remain on either side
of a 1→6 branch
-Glucantransferase then transfers a trisaccharide unit
from one branch to another, exposing the 1→6 branch
point
11

12

- Hydrolysis of the 1→6 linkages is effected by the
debranching enzyme which releases one glucose
molecule, and further phosphorylase action can proceed
-The action of phosphorylase, glucan transferase and
debranching enzyme leads to complete breakdown of
glycogen
-Glucose 6- phosphate can be formed from glucose 1
phosphate by the action of phosphoglucomutase
- In the liver and kidney (but not in muscle or brain),
glucose 6-phosphatase hydrolyzes glucose 6- phosphate
to glucose that is exported leading to increased blood
glucose concentration
...
The hydrolytic enzyme
glucose 6-phosphatase enables glucose to leave the
cells

-Consequently glucose 6-phosphate is retained by
muscle or brain , which need a large amount of fuel
for the generation of ATP
-In contrast glucose is not the major fuel for the liver –
the liver stores and releases glucose primarily for
benefit of other tissues
...
It is
inactivated by the removal of a phosphate by protein
phosphatase-1 to form phosphorylase b
Reactivation requires rephosphorylation catalyzed by
phosphorylase kinase
17

Phosphorylase activation differs between liver and
muscle
In liver
• Glucagon leads to formation of cAMP and activation
of phosphorylase
• Glycogenolysis in liver can also be

cAMP

independent

18

-epinephrine

and

norepinephrine

can

mediate

stimulation of glycogenolysis
- This involves cAMP-independent mobilization of

Ca
the

2+

from mitochondria into the cytosol followed by
stimulation

of

a

Ca2+/calmodulin–sensitive

phosphorylase kinase

-Vasopressin, oxytocin, angiotensin II acting through
Ca 2+ or the phosphatidylinositol bisphosphate pathway
19

In the muscle
• Muscle lacks both glucagon receptors and glucose 6phosphatase
• Therefore muscle glycogen can not be mobilized to
replenish blood glucose
• Muscle glycogenolysis is activated:
1
...
Hormone independent mechanisms
-The influx of Ca 2+ into the muscle cytoplasm in
response to nerve stimulation activates the basal,
unphosphorylated form of phosphorylase kinase by
the action of Ca 2+-calmodulin complex
...
protein
kinase (inactive)

Glycogen synthase a (active)

cAMP-dep
...
protein
kinase (inactive)

cAMP-dep
...

Inhibition of glycogenolysis enhances net glycogenesis

25

Dephosphorylation of phosphorylase, phosphorylase kinase
a, and glycogen synthase b is catalyzed by a single
enzyme of wide specificity- protein phosphatase-1
Thus, glycogenolysis can be terminated and glycogenesis
can be stimulated synchronously, and vice versa
The control of the synthesis and degradation of glucose in
the liver is central to the regulation of blood glucose
The liver senses the concentration of glucose in the blood
and takes up or releases glucose accordingly
26

Glycogen Storage Diseases
Type

Defective
Enzyme

Organ

1
von
Gierke’s
disease

G6phosphatase

Liver and
kidney

II Pompe’s
disease

α-1,4Glucosidase
(lysosomal)

All organs

III Cori’s
disease

Debranching
enzyme

Muscle & liver

IV
Andersen’s Branching
enzyme
disease

Liver and
spleen

Glycogen

Normal

Normal
Massive

Short outer
branches

Very long outer
branches
...
Death usually
before 2 years
Like I but
milder
Liver cirrhosis
...

Death usually
before 2 years
27

V McArdle’s Phosphorylae
disease
VI Her’s
disease
VII Tarui’s
disease

VIII

Phosphorylase

Muscle

Moderately
increased
...

Normal
structure

Increased
amount
...

Mild
hypoglycaemia

XXX
28

Summary
• Glycogen breakdown requires the interplay of several
enzymes
• Phosphorylase is regulated by allosteric interactions and
reversible phosphorylation

• Epinephrine and glucagon signal the need for glycogen
breakdown
• Glycogen is synthesized and degraded by different
pathways
• Glycogen breakdown and synthesis are reciprocally
regulated
29



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