GLYCOGENOLYSIS and GLYCOGENESIS

Lecturer: Maria Esperanza E. Uy, MD, FPCP (11-08-2012)

Edited to Word Format by

Learning Objectives:
What are the steps glycogen breakdown and
synthesis?
What are the central enzymes in glycogen
mobilization and synthesis?
How are glycogen mobilization and synthesis
coordinated?
What are the different glycogen storage diseases
and why is biochemical understanding of each is
important?

Glycogenolysis breakdown of glycogen to glucose

or G6P
Glycogenesis synthesis of glycogen

These 2 processes are especially occurring in

muscle & liver

Glycogen Granules
Abundant in liver of well-fed animals but
absent after 24 hrs of fasting; or after heavy
exercise
Granules also contain the enzymes that
catalyze its formation and use.

STORAGE
The polymeric nature of glycogen allows Muscle glycogen is a fuel reserved for the
energy to be sequestered without the production of ATP within that tissue
problems of osmotic effects that glucose whereas liver glycogen is a glucose reserve
would cause. for the maintenance of blood concentration
Primarily stored in the MUSCLE and LIVER
In humans, liver glycogen stores are typically
adequate for up to 12 hrs. without the support
of gluconeogenesis

Glycogen Storage
Glycogen concentration is higher in the liver
than in muscle, but
More glycogen is stored in the skeletal muscle
because there are more skeletal muscles in
the body than there is liver tissue.
In the liver, glycogen synthesis and
degradation are regulated to maintain blood-
glucose levels as required to meet the needs
of the body as a whole.
In the muscle, these processes are regulated
to meet the energy needs of the muscle itself.
Glycogen - storage form of fuel
o Composed of glucosyl residues, mostly
linked together by - 1,4 glycosidic Glycogen Breakdown Requires Several Enzymes
linkages. Branches arise from frequent Breakdown of glycogen to provide glucose 6-
- 1,6 glycosidic linkages phosphate for further metabolism requires
Glycogen Tree - branches at every 4th four enzyme activities:
glucosyl residue within the more central core o One to degrade glycogen
of the molecule and less in the outer region o 2 enzymes to remodel glycogen so that
it remains a substrate for degradation
o One to convert the product of glycogen
breakdown into a form suitable for
further metabolism

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Glycogen Degradation

Phosphorylase Cleaves Glycogen to Release

Glucose 1-Phosphate

Glycogen phosphorylase, the key regulatory

enzyme in glycogen breakdown, cleaves
glycogen by the addition of orthophosphate
(Pi) to yield glucose 1- phosphate
(phosphorolysis).
Pi splits the glycosidic linkage between C-1 of
the terminal residue and the C-4 of the
adjacent one, cleaving
The bond between the C-1 carbon atom and
the glycosidic oxygen atom, and the ACTION OF GLYCOGEN PHOSPHORYLASE
configuration at C-1 of the newly released Hydrolytic action always at the NON-
glucose 1-P is retained REDUCING end
1-4 glycosidic link cleaved by
PHOSPHOROLYSIS

Phosphorolytic Advantages of Glycogen

Breakdown
The phosphorolytic cleavage of glycogen is
energetically advantageous because the
released sugar is already phosphorylated.
There are no transporters in the muscle cells
for glucose 1-phosphate, which is negatively
charged under physiologic conditions, so it
cannot be transported out of the cell.

Debranching Enzyme is Required for

Glycogenolysis
Glycogen phosphorylase is specific -1,4
glycosidic linkages
It stops attacking -1,4 - glycosidic linkages
when it reaches a residue 4 glucosyl residues
from an -1,6- branch point
Phosphorylase-limit dextrin is the glycogen
molecule that has been degraded to the limit.

How can the remainder of the glycogen molecule

be degraded for use as a fuel?
Two additional enzymes, a transferase and -
1,6-gluco
sidase, remodel the glycogen for continued This now exposes a single residue joined by an
degradation by the phosphorylase. -1,6-glycosidic linkage
The transferase shifts a block of three glucosyl The debranching enzyme then hydrolyzes the
residues from an outer branch to the other. -1,6-glycosidic bond, releasing a free glucose
molecule.

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 The cooperative & repetitive action of
phosphorylase & debranching enzyme results
in complete breakdown of glycogen to glucose
-1- PO4 & glucose.
Phosphoglucomutase converts glucose 1-
phosphate into glucose 6-phosphate so that it
can enter the metabolic mainstream.

Liver Contains Glucose 6-Phosphatase, a

Hydrolytic Enzyme Absent from Muscle
A major function of the liver is to maintain a
nearly constant level of glucose in the blood.
The liver releases glucose into the blood
during muscular activity and between meals.
The released glucose is taken up by the brain,
skeletal muscle and RBCs.
The liver contains glucose 6-phosphatase that
enables glucose to leave that organ

Phosphorylase is Regulated by Allosteric

Interactions and Reversible Phosphorylation
Phosphorylase is regulated by several
allosteric effectors that signal the energy
state of the cell as well as reversible
phosphorylation, which is responsive to
hormones such as insulin, epinephrine and
glucagon.
Debranching Enzyme
The differences in the control of glycogen
Allows phosphorylase to continue to degrade
metabolism between the skeletal muscle and
glycogen
the liver is the fact that the muscle uses
Bifunctional enzyme
glucose to produce energy for itself, whereas
A. 1,4 1,4-glucan transferase activity the liver maintains glucose homeostasis of
B. -1,6 glucosidase activity the organism as a whole

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GLYCOGEN SYNTHESIS

Glycogen is Synthesized and Degraded by

Different Pathways
Glycogen is synthesized by a pathway that
utilizes uridine diphosphate glucose (UDP-
glucose) rather than glucose 1-phosphate as
the activated glucose donor.
UDP-glucose is synthesized from glucose 1-
phosphate and the nucleotide uridine
triphosphate (UTP) in a reaction catalyzed by
UDP-glucose pyrophosphorylase.
The above reaction liberates the outer 2
phosphoryl residues of UTP as pyrophosphate.

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 Glycogen Synthase Catalyzes the Transfer of
Glucose from UDP-Glucose to a Growing Chain
Glycogen Synthase transfer the activated
glucosyl moiety of UDP glucose to the carbon
4 of a glucosyl residue of the growing chain to
form a new glycosidic bond at the hydroxyl
group of C1of the activated sugar.
The reducing end of glucose (C1) is always
added to the non- reducing end (C4) of a
glucosyl residue of the glycogen chain

A Branching Enzyme Forms -1,6 Linkages Branching increases the rate of glycogen
Glycogen synthase cannot form the 1,6- synthesis and degradation
glycosidic linkages
Once an amylose chain of at least 11 residues
has been formed, a branching enzyme,1,4-
glucan branching enzyme removes a block of
about 7 glucosyl residues from a growing chain
and transfer it to another chain to produce an
-1,6 linkage.
The new branch has to be introduced at least
4 glucosyl residues from the nearest branch
points
The creation of the highly branched structure
of glycogen requires the concerted efforts of
glycogen synthase and branching enzyme.
Branching is important because it increases
the solubility of glycogen.
Branching creates a large number of terminal
residues, the sites of action of glycogen
phosphorylase and synthase.

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Glycogenin is Required as a Primer for Glycogen 3. Fat cannot be converted to glucose to
Synthesis maintain blood glucose levels required by the
brain

Why not Store it as Free Glucose? Why Waste

ATP Making a Polymer Out of Glucose?
It would cost ATP to pump glucose into a
cell against a concentration gradient, and its
concentration would have to reach about 400
mm in liver cells to match the glucose
reserve provided by the usual liver glycogen
content.
Unless balanced by outward movement of
some other osmotically active compound,
accumulation of glucose would cause
considerable uptake of water with osmotic
lysis of the cell.

Glycogen Synthesis and Degradation are Highly

Regulated
Glycogen synthase and glycogen phosphorylase
SPECIAL FEATURES OF GLYCOGENOLYSIS &
are the regulatory enzymes of glycogen
GLYCOGENESIS
synthesis and degradation respectively.
Both catalyze non-equilibrium reactions, &
Why Store Glucose as Glycogen & NOT FAT? both are subject to control by allosteric
1. Fat cannot be mobilized nearly as rapidly as
effectors and covalent modification
glycogen
2. Fat cannot be used as a source of energy in
the absence of O2

Regulation of Glycogen Synthase and Glycogen Phosphorylase

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A Biochemical Understanding of Glycogen-Storage
Diseases is Possible
Edgar von Gierke described the 1st glycogen
storage disease in 1929.
o A patient with this disease had a huge
abdomen caused by a massive enlargement
of the liver.
o There is pronounced hypoglycemia
between meals.
o The blood glucose does not rise on the
administration of epinephrine and glucagon
o An infant with this disease may have
convulsions because of low blood glucose
level
o The enzymatic defect in von Gierke
disease was elucidated in 1952 by Carl and
Gerty Cori.
o Glucose 6-phosphatase is missing from the
liver of a patient with this disease.
o This finding was the first demonstration of
an inherited deficiency of a liver enzyme.
o The liver glycogen is normal in structure
but present in abnormally large amounts

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 o The absence of glucose 6-phosphatase in o The presence of excess G 6-P triggers an
the liver causes hypoglycemia because increase glycolysis in the liver, leading to
glucose could not be formed from G 6-P high lactate and pyruvate in the blood.
o The G 6-P does not leave the liver, o Patients with von Gierke disease also have
because it cannot cross the plasma an increase dependence on fat
membrane. metabolism.
o fasting hypoglycemia, lactic acidemia,
hyperlipidemia, & hyperuricemia with
gouty arthritis

Pompes Disease Type II

o caused by the absence of - 1,4
glucosidase (or acid maltase), normally
found in lysosomes
o accumulation of glycogen mostly in
lysosomes in virtually every tissue
o Severe hypoglycemia, massive
cardiomegaly & cardiomyopathy occur &
death results from heart failure

Coris Disease or Type III

o Caused by deficiency of glycogen
debranching enzyme, -1,6 glucosidase.
o Glycogen accumulates because only the
outer branches can be removed by
phosphorylase
o hepatomegaly & other clinical
manifestation are similar to, but milder
than those in Von Gierkes disease

Andersens Disease or Type IV

o Deficiency of the branching enzyme,
glucosyl 4:6 transferase
o Normal amount of glycogen but with very
long outer branches
o Liver cirrhosis and death before 2 years of
age

McArdles Disease or Type V

o caused by the absence or deficiency of
skeletal muscle glycogen phosphorylase
o The liver enzyme is normal
o patients suffer from painful muscle cramps
and are unable to perform strenuous
exercise because muscle glycogen stores
are not available to the exercising muscle
o the normal increase in plasma lactate
following exercise is absent

Hers Disease or Type VI

o Deficient enzyme is liver phosphorylase
o Mild hepatomegaly and hyperlipidemia
o Mild hypoglycemia or no symptoms at all

GSD Type VII

o Enzyme deficient is phosphofructokinase
o Patients have painful muscle cramps with
GLYCOGEN STORAGE DISEASES exercise

Von Gierkes Disease or Type 1 GSD Type VIII

o most common o Phosphorylase kinase (liver) is the enzyme
o deficiency of liver, intestinal mucosa & deficient
kidney G 6-phosphatase o Mild hepatomegaly and hypoglycemia
o diagnosis possible by intestinal biopsy o Growth retardation, delayed motor
development and increased blood lipids

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