GLYCOGEN

SYNTHESIS
AND REGULATION
PRESENTER DR.MANENTO E.MTANGO

FACILITATORS: PROF KAJUNA

AND
DR.BONIFACE
INTRODUCTION
Glycogen is a polymer of glucose
residues.
Glycogen synthesis is of importance in
almost every tissue especially in muscle
and liver.The liver has tremendous
capacity for storing glycogen. In a well
fed human content of liver glycogen can
account for as much as 10% weight of
this organ.
 Muscle stores less when expressed on
the same basis a maximum of only 1- 2
% of its weight. However since the
average person has more muscle than
liver,there is about twice as much total
muscle glycogen as liver glycogen.
 Glycogen is present in the cytosol in the
form of granules ranging in diameter
from 10 to 40 nm. These granules
contains regulatory proteins as well as
enzymes that catalyze the synthesis and
degradation of glycogen.
ROLE OF GLYCOGEN
STORES

Muscle and liver glycogen serve

complitely different roles.Glycogen
serves as a fuel reserve for the synthesis
of ATP within muscle,whereas liver
glycogen serves as glucose reserve for
the maintanance of blood glucose
concentration.
Liver glycogen levels varies greatly in
response to the intake of food,
accumulating to higher levels shortly
after meal and then decreasing slowly as
it is mobilized to maintain a nearly
constant blood glucose level.
STRUCTRURE OF GLYCOGEN

Glycogen is a polymer of glucose

residues linked mainly by a(1- 4)
glycosidic linkages. Branches at about
every 10th residue are created by & 1,6
glycosidic bond.
 CH2OH CH2OH
H O O
glycogen
H H H
H H
OH H OH H 1
O
OH
O
H OH H OH

CH2OH CH2OH 6 CH2 CH2OH CH2OH

H O H H O H H 5 O H H O H H O H
H H H H H
OH H OH H OH H 1 4 OH H OH H
4 O O
O O OH
OH 2
3
H OH H OH H OH H OH H OH
STEPS IN GLYCOGEN
SYTHESIS
Glycogen synthesis is, unlike its
breakdown, endergonic. This means that
glycogen synthesis requires the input of
energy. Energy for glycogen synthesis
comes from UTP, which reacts with
glucose-1-phosphate, forming UDP-
glucose, in reaction catalysed by UDP-
glucose pyrophosphorylase.
 Synthase cannot start from scratch
needs a primer
Activated glucosyl unit of UDP-glucose

is transifered to the hydroxyl group at

a terminus of glycogen to form an & 1-
4 glycosidic linkage.UDP is displaced
by terminal OH of growing glycogen
molecule.
Glycogenin starts a new glycogen

chain, bound to itself

 Glycogen is synthesized from monomers
of UDP-glucose by the enzyme glycogen
synthase, which progressively lengthens
the glycogen chain with (14) bonded
glucose. As glycogen synthase can only
lengthen an existing chain, the protein
glycogenin is needed to initiate the
synthesis of glycogen. The glycogen-
branching enzyme, amylo (14) to
(16) transglycosylase, catalyzes the
 transfer of a terminal fragment of 6-7
glucose residues from a nonreducing end
to the C-6 hydroxyl group of a glucose
residue deeper into the interior of the
glycogen The branching enzyme can act
upon only a branch having at least 11
residues, and the enzyme may transfer
to the same glucose chain or adjacent
glucose chainsmolecule.
 O

CH2OH HN

H O H
H O N
OH H O O

OH O P O P O CH2
O

H OH O O H H
H H
UDP-glucose OH OH
Uridine diphosphate glucose (UDP-
glucose) is the immediate precursor
for glycogen synthesis.
As glucose residues are added to
glycogen, UDP-glucose is the substrate
and UDP is released as a reaction
product.
 O
UDP-Glucose Pyrophosphorylase
CH2OH HN

H O H
H O N
OH H O O O O

OH O P O +
O P O P O P O CH2
O

H OH O O O O H H

glucose-1-phosphate UTP H
OH OH
H

PPi O

CH2OH HN

H O H
H O N
OH H O O

OH O P O P O CH2
O

H OH O O H H
H H
UDP-glucose OH OH
1. Isomerization; G6P -> G1P
2. Activation by UTP
3. Glycogenin priming
4. Extension by Glycogen Synthase
5. Branching
6. Repeat 4 & 5
UDP-glucose is formed from glucose-
1phosphate:
glucose-1-phosphate + UTP

UDP-glucose + PPi
PPi + H2O 2 Pi
Overall:
glucose-1-phosphate + UTP

UDP-glucose + 2 Pi
Spontaneous hydrolysis of the ~P bond
in PPi (P~P) drives the overall reaction.
Cleavage of PPi is the only energy cost
for glycogen synthesis (one ~P bond
per glucose residue).
GLYCOGENIN/GLYCOGEN
SYNTHASE ACTION
Glycogenin autocatalyses the addition of some
eight glucose units.
UDP glucose is the donor in this
autoglycosylation.
Glycogen synthase is catalytically efficient only
when is bound to glycogenin and this has two
effects: the no of glycogen granules determined
by no of glycogenin molecules,elongation stops
when synthase is no longer in contact with
glycogenin is a molecular divice for setting of
biological structure.
BRANCHING ENZYMES
This enzymes forms the &1-6 linkages
that make glycogen a branched polymer
and this increases the solubility of
glycogen.
Further more branching creates a large
number of terminal residues,the sites of
action of phosphorylase and synthase,
hence branching increases rate of
synthesis and degradation of glycogen.
 Branching occurs after a number of
glucosyl residues are joined in & 1- 4
linkage by glycogen synthase.
A branch is created by the breaking of &
1- 4 and the formation of an & 1- 6 link.
REGULATION OF GLYCOGEN
SYNTHESIS
Both synthesis & breakdown of glycogen are
spontaneous.
If both pathways were active simultaneously
in a cell, there would be a "futile cycle"
with cleavage of one ~P bond per cycle
(in forming UDP-glucose).
To prevent such a futile cycle, Glycogen
Synthase and Glycogen Phosphorylase are
reciprocally regulated, by allosteric
effectors and by phosphorylation.
Glycogen Phosphorylase in muscle is
subject to allosteric regulation by AMP,
ATP, and glucose-6-phosphate. A
separate isozyme of Phosphorylase
expressed in liver is less sensitive to
these allosteric controls.
AMP (present significantly when ATP
is depleted) activates Phosphorylase,
promoting the relaxed conformation.
ATP & glucose-6-phosphate,
which both have binding sites that
overlap that of AMP, inhibit
Phosphorylase, promoting the tense
conformation.
Thus glycogen breakdown is inhibited
when ATP and glucose-6-phosphate
are plentiful.
Glycogen Synthase is allosterically
activated by glucose-6-phosphate
(opposite of the effect on Phosphorylase).
Thus glycogen synthesis is activated when
glucose-6-phosphate is plentiful.
These controls benefit the cell because it is
more useful to a cell to store glucose as
glycogen when the input to Glycolysis
(glucose-6-phosphate), and the main product
of Glycolysis (ATP), are adequate.
The cAMP cascade induced in liver by
glucagon or epinephrine has the
opposite effect on glycogen
synthesis.
Glycogen Synthase is directly
phosphorylated by cAMP-Dependent
Protein Kinase, as well as by
Phosphorylase Kinase.
Phosphorylation of Glycogen Synthase
promotes the "b" (less active) conformation.
The cAMP cascade inhibits glycogen
synthesis.
Instead of being converted to glycogen,
glucose-1-phosphate in liver may be
converted to glucose-6-phosphate, and
dephosphorylated for release to the blood.
 Insulin, produced in response to high
blood glucose, triggers a separate signal
cascade that leads to activation of
Phosphoprotein Phosphatase.
This phosphatase catalyzes removal of
regulatory phosphate residues from
Phosphorylase, Phosphorylase Kinase, &
Glycogen Synthase enzymes.
Thus insulin antagonizes effects of the
cAMP cascade induced by glucagon &
epinephrine.
Glycogen storage
diseases
Glycogen storage diseases are
genetic enzyme deficiencies that result
in excessive glycogen accumulation
within cells. Additional symptoms
depend on the particular enzyme that is
deficient.
THANKING

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