Glycogen Metabolism

By
Prof. A. Kwena
 Introduction
• Glycogen is a storage polysaccharide found in
animal tissue
• It is especially abundant in liver and muscle
• Consists of D-glucose in 2(1-4) linkage.
• It is more highly branched and the branch
linkage are 2(1-6).
• Glycogen is readily hydrolysed by α and β
amylases to form glucose and maltase
respectively.
• Synthesis of glycogen from 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.
• The activation of glucose to be used for
glycogen synthesis is carried out by the
enzyme UDP-glucose pyrophosphorylase.
• This enzyme exchanges the phosphate on C-1
of glucose-1-phosphate for UDP.
• The energy of the phospho-glycosyl bond of
UDP-glucose is utilized by glycogen synthase
to catalyze the incorporation of glucose into
glycogen.
• UDP is subsequently released from the
enzyme. 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.
Biosynthesis of glycogen
Glucose
1.
Glucose 6 phosphate
2.
Glucose1,6, bisphosphate
3.
Glucose-1-phosphate
4.
Uridine diphosphate glucose
5.
1-4 Glucosyl units
6.
GLYCOGEN
(1-4 and 1-6 glucosyl units)
 Enzymes
• 1.Glucokinase
• 2.
• 3.Phosphoglucomutase
• 4.UDP Glucose pyrophosphorylase
• 5.Glycogen synthase
• 6. branching enzyme.
Glycogen Synthesis
 Regulation of Glycogen Synthesis

• Glycogen synthase is a tetrameric enzyme

consisting of 4 identical subunits.
• The activity of glycogen synthase is regulated
by phosphorylation of serine residues in the
subunit proteins.
• Phosphorylation of glycogen synthase reduces
its activity towards UDP-glucose.
• When in the non-phosphorylated state,
glycogen synthase does not require glucose-6-
phosphate as an allosteric activator, when
phosphorylated it does.
• The two forms of glycogen synthase are
identified by the same nomenclature as used
for glycogen phosphorylase.
• The unphosphorylated and most active form is
synthase-a and the phosphorylated glucose-6-
phosphate-dependent form is synthase-b
shift.
 Glycogen Synthesis
UTP UDP + 2 P i
glycogen(n) + glucose-1-P glycogen(n + 1)

Glycogen Phosphorylase Pi

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 Glucose
Hexokinase or Glucokinase
Glucose-6-Pase
Glucose-1-P Glucose-6-P Glucose + Pi
Glycolysis
Pathway
Pyruvate
Glucose metabolism in liver.

Glucose-6-phosphate may enter Glycolysis or (mainly in

liver) be dephosphorylated for release to the blood.
Liver Glucose-6-phosphatase catalyzes the following,
essential to the liver's role in maintaining blood glucose:
glucose-6-phosphate + H2O  glucose + Pi
Most other tissues lack this enzyme.
• Phosphorylase kinase
• Glucan transferase
• Debranching enzyme

• Phosphoglucomutase
Glycogen breakdown
glycogen

glucose-1-P
Glucose-6-Phosphatase
glucose-6-P glucose + Pi

fructose-6-P
Phosphofructokinase
fructose-1,6-bisP

Glycolysis continued
 Glycogenolysis cont’d.

• Degradation of stored glycogen, termed

glycogenolysis, occurs through the action of
glycogen phosphorylase.
• The action of phosphorylase is to
phosphorolytically remove single glucose
residues from α-(1,4)-linkages within the
glycogen molecules.
• The product of this reaction is glucose-1-
phosphate. The advantage of the reaction
proceeding through a phosphorolytic step is
that:
• 1. The glucose is removed from glycogen in an
activated state, i.e. phosphorylated and this
occurs without ATP hydrolysis.
• 2. The concentration of Pi in the cell is high
enough to drive the equilibrium of the
reaction in the favorable direction since the
free energy change of the standard state
reaction is positive.
Glycogenolysis (Breakdown)
Glycogen Storage
Diseases are genetic glycogen
enzyme deficiencies
associated with excessive glucose-1-P
glycogen accumulation
Glucose-6-Phosphatase
within cells.
glucose-6-P glucose + Pi
Some enzymes whose
deficiency leads to fructose-6-P
glycogen accumulation Phosphofructokinase
are part of the inter- fructose-1,6-bisP
connected pathways
shown here. Glycolysis continued
Regulation by covalent modification (phosphorylation):
The hormones glucagon and epinephrine activate
G-protein coupled receptors to trigger cAMP cascades.
 Both hormones are produced in response to low
blood sugar.
 Glucagon, which is synthesized by a-cells of the
pancreas, activates cAMP formation in liver.
 Epinephrine activates cAMP formation in muscle.
 Symptoms, in addition to
Glycogen Storage Disease
glycogen accumulation
Type I, liver deficiency of hypoglycemia (low blood
Glucose-6-phosphatase (von glucose) when fasting, liver
Gierke's disease) enlargement.
Type IV, deficiency of liver dysfunction and early
branching enzyme in various death.
organs, including liver
(Andersen's disease)
Type V, muscle deficiency of muscle cramps with exercise.
Glycogen Phosphorylase
(McArdle's disease)
Type VII, muscle deficiency of inability to exercise.
Phosphofructokinase.
 Glycogen Metabolism
cont’d

• Glycogen Metabolism
• Glycogen is a readily mobilized storage form of
glucose. It is a very large, branched polymer of
glucose residues that can be broken down to
yield glucose molecules when energy is needed.
• Most of the glucose residues in glycogen are
linked by α-1,4-glycosidic bonds. Branches at
about every tenth residue are created by α-1,6-
glycosidic bonds.
• The two major sites of glycogen storage are the
liver and skeletal muscle.
• The concentration of glycogen is higher in the
liver than in muscle (10% versus 2% by weight),
but more glycogen is stored in skeletal muscle
overall because of its much greater mass.
• Glycogen is present in the cytosol in the form of
granules ranging in diameter from 10 to 40 nm .
• In the liver, glycogen synthesis and
degradation are regulated to maintain blood-
glucose levels as required to meet the needs
of the organism as a whole.
• In contrast, in muscle, these processes are
regulated to meet the energy needs of the
muscle itself.
 An Overview of Glycogen Metabolism (Summary)

Fates of Glucose 6-Phosphate

• Glucose 6-phosphate derived from glycogen can
• (1) be used as a fuel for anaerobic or aerobic
metabolism as in, for instance, muscle;
• (2) be converted into free glucose in the liver and
subsequently released into the blood;
• (3) be processed by the pentose phosphate pathway
to generate NADPH or ribose in a variety of tissues.
• Glycogen degradation and synthesis are
relatively simple biochemical processes.
Glycogen degradation consists of three steps:
• (1) the release of glucose 1-phosphate from
glycogen,
• (2) the remodeling of the glycogen substrate to
permit further degradation, and
• (3) the conversion of glucose 1-phosphate into
glucose 6-phosphate for further metabolism.
• The glucose 6-phosphate derived from the
breakdown of glycogen has three fates
• (1) It is the initial substrate for glycolysis,
• (2) it can be processed by the pentose phosphate
pathway to yield NADPH and ribose derivatives; and
• (3) it can be converted into free glucose for release
into the bloodstream.
• This conversion takes place mainly in the liver and to
a lesser extent in the intestines and kidneys.
• Glycogen synthesis requires an activated form
of glucose, uridine diphosphate glucose (UDP-
glucose), which is formed by the reaction of
UTP and glucose 1-phosphate.
• UDP-glucose is added to the nonreducing end
of glycogen molecules.
• As is the case for glycogen degradation, the
glycogen molecule must be remodeled for
continued synthesis.
• The regulation of these processes is quite
complex. Several enzymes taking part in
glycogen metabolism allosterically respond to
metabolites that signal the energy needs of
the cell.
• These allosteric responses allow the
adjustment of enzyme activity to meet the
needs of the cell in which the enzymes are
expressed.
• Glycogen metabolism is also regulated by
hormonally stimulated cascades that lead to
the reversible phosphorylation of enzymes,
which alters their kinetic properties.
• Regulation by hormones allows glygogen
metabolism to adjust to the needs of the entire
organism
• By both these mechanisms, glycogen
degradation is integrated with glycogen
synthesis.