Glycogen

Metabolism
Introduction
• In animals, glycogen serves as a
carbohydrate reserve.

• The human body can store up to 320

gram of glycogen.

• Liver and muscles are the main sites

for glycogen storage.
Liver glycogen
• Liver has up to 10% of its weight as
glycogen.

• Is mainly stored as a glucose

reservoir for other tissues.

• Is used to maintain blood glucose

level in post-absorptive state.
Liver glycogen
• Level changes considerably with the
feeding condition.

• May be depleted after long period of

fasting
Muscle glycogen
• Is mainly stored as a readily available
source of glucose-6-phosphate for
glycolysis (energy for muscle
contraction and glycerol synthesis)

• It is not involved in maintenance of

blood glucose level. Muscles do not
possess glucose-6-phosphatase.
Storage of carbohydrate in postabsorptive
normal adult humans (70 kg).
Glycogen Structure
• Glycogen is a branched homopolymer
of glucose.

• Most glucose residues in glycogen are

linked by α1→4glycosidic bonds.

• A branch chain linked by α1→6

glycosidic bonds is found almost every
12 residues.
Glycogenesis
 Glycogen Synthesis
(Glycogenesis)
• Occurs in fed state condition when
there is plenty of glucose entering cells.

• Glucose is converted to G-6-P by

glucokinase in liver and hexokinase in
muscles.

• G-6-P is then isomerized to G-1-P by

phosphohexose mutase.
 Glycogen Synthesis
• G-1-P will then be activated by reaction
with UTP catalyzed by UDP-glucose
pyrophosphorylase to produce UDP-
glucose (activate glucose).

• The energy of the phospho-glycosyl bond

of UDP-glucose is utilized by glycogen
synthase to catalyze the incorporation of
glucose into glycogen.
Glycogen Synthesis (Glycogenesis)
• Synthesis of glycogen from UDP-
glucose is carried out by the enzyme
glycogen synthase.

• This enzyme utilizes UDP-glucose as

one substrate and the non-reducing
end of glycogen as another.

• Glycogen synthase catalyzes the

formation of α1-4 bonds.
 Glycogen Synthesis
• The α-1,6 branches in glucose are
produced by amylo-(1,4 - 1,6)-
transglycosylase, also termed the
branching enzyme.

• This enzyme transfers a terminal

fragment of 6-7 glucose residues (from a
polymer at least 11 glucose residues
long) to an internal glucose residue at
the C-6 hydroxyl position.
Priming glycogen synthesis
• A protein called glycogenin is located at
the core of glycogen molecules.

• Glycogenin catalyzes its own

glycosylation, attaching C-1 of a UDP-
glucose to a tyrosine residue on the
enzyme.

• The attached glucose then serves as the

primer required by glycogen synthase.
Regulation of Glycogen Synthesis
• Glycogen synthase is a tetrameric
enzyme consisting of 4 identical
subunits.

• The activity of glycogen synthase is

regulated by phosphorylation.

• Phosphorylation of glycogen synthase

reduces its activity towards UDP-
glucose.
• Glycogen synthase is allosterically
activated by the pathway substrate G-6-
P when it is phosphorylated.

• When in the non-phosphorylated state,

glycogen synthase is not affected by
glucose-6-phosphate as an allosteric
activator.
Glycogenolysis
 Glycogen degradation
(Glycogenolysis)

• Degradation of stored glycogen occurs

through the action of glycogen
phosphorylase.

• The action of phosphorylase is to

remove single glucose residues from
a-(1,4)-linkages within the glycogen
molecules (phosphorolysis).
• The product of phosphorlysis is G-1-P.

• The G-1-P produced by the action of

phosphorylase is converted to G-6-P by
phosphoglucomutase
• An additional advantage of
releasing phosphorylated glucose
from glycogen ensures that the
glucose residues do not freely
diffuse from the cell.
• G-1-P is then converted to G-6-P
by phosphohexose mutase.
 Glucose-6-phosphatase
• The conversion of G-6-P to glucose,
which occurs in the liver, kidney and
intestine, by the action of glucose-6-
phosphatase does not occur in skeletal
muscle ( lack this enzyme).
• The glucose released from glycogen
stores of muscle will only be oxidized
in the glycolytic pathway within the
myocytes.

• In the hepatocytes the action of G-6-

Phosphatase allows glycogenolysis to
generate free glucose for maintaining
blood glucose levels.
 The Debranching Enzyme
• Glycogen phosphorylase cannot
remove glucose residues from the
branch points (α-1,6 linkages) in
glycogen.

• The activity of phosphorylase ceases 4

glucose residues from the branch
point.
The Debranching Enzyme

• The removal of the branch point

glucose residues requires the action
of debranching enzyme (glucan
transferase) which contains 2
activities: glucotransferase and
glucosidase
• The transferase activity removes the
terminal 3 glucose residues of one
branch and attaches them to a free C-
4 end of a second branch.

• The glucose in a-(1,6)-linkage at the

branch is then removed by the action
of glucosidase.
• Glucose residues removed by
glucosidase are uncharged since the
glucosidase-catalyzed reaction is not
phosphorylytic.
Regulation of glycogen metabolism is
effected by a balance in activities between
glycogen synthase & phosphorylase

• Inhibition of glycogenolysis enhances

net glycogenesis, and inhibition of
glycogenesis enhances net
glycogenolysis.
• Both phosphorylase kinase and
glycogen synthase may be reversibly
phosphorylated in more than one site
by separate kinases and phosphatases.
Control of phosphorylase in muscle
Control of glycogen synthase in muscle
 Glycogen Storage Diseases

• A group of hereditary disorders result

from various mutations in the genes
encoding the enzymes of glycogen
metabolism.

• The severity of these disease varies

with the type of the mutation and the
role of the deficient enzyme.