HB09 :Glycogen Metabolism

R Sanjeev, PhD
Dept. of Human Biology
FHCS
 Significance of Glycogen Metabolism
• Glycogen is not as reduced as fatty acids are
and consequently not as energy rich.

Then, why do animals store any energy as

glycogen?
Why not convert all excess fuel into fatty
acids?
 Significance of Glycogen Metabolism

• Constant source of blood glucose is an

absolute requirement for human life.

• Glycogen's role in maintaining blood-glucose

levels is especially important because glucose
is virtually the only fuel used by the brain
& cells with few / no mitochondria (Eg:
RBC).
Significance of Glycogen Metabolism

• Moreover, the glucose from glycogen is

readily mobilized and is therefore a good
source of energy for sudden, strenuous
activity.
• Unlike fatty acids, the released glucose can
provide energy in the absence of oxygen and
can thus supply energy for anaerobic
activity
Blood glucose can be obtained by
1) Diet (sporadic / Irregular- not always a reliable source of
blood glucose)
2) Gluconeogenesis (slow in responding)
3) Glycogenolysis
 Structure of glycogen particles

Glycogen is
principally stored
in the cytosol of
liver and skeletal
muscle cells mainly
Liver Cell
Glycogen Function
Why excess glucose is stored as glycogen
not as glucose?

Glycogen is insoluble thus, storing it as

glycogen will not upset the osmotic pressure
rather than glucose which is soluble in water
and if it is stored as glucose it will disturb the
osmotic pressure(hypertonic) that will cause
the cell to lyse
 Glycogen Metabolism

1. Glycogenesis:
Formation of glycogen
(de novo or enlarge)

2. Glycogenolysis:
Glycogenolysis is a
catabolic process; the
breakdown of glycogen
to glucose units.
 Luis Leloir
Nobel Prize in Chemistry, 1970

“ for his discovery of sugar

nucleotides and their role
in the biosynthesis of
carbohydrates”
"Why do students fall asleep during lectures?"
The problem is that so many lecturers see teaching as a one-way communication. If a
student is not contributing to the communication, they lose focus and many literally
go to sleep.

There are other triggers for sleeping during lessons, such as eating a large meal
immediately before the lesson, poor ventilation in the classroom, and tired
students.
 Glycogenesis
The synthesis of glycogen
an energy consuming pathway
Glycogenesis: formation of glycogen

REQUIRES

Glycogenin,
Glycogen synthase,
 Glycogen-branching enzyme
 UDP-glucose
 Pyrophosphorylase
 Glycogenesis

• Glycogenesis can be separated into two

phases:
1. Formation of new glycogen particle
2. Enlargement of existing glycogen particle.

• Both of them require UDP-glucose as

precursor, which is synthesized by UDP-
glucose pyrophsphorylase.
 GLYCOGENESIS

• Insulin stimulates hepatocytes & skeletal

muscle cells to carry out this reaction

• The body can store around 500g of glycogen

(75 % in Sk. Mus & 25% in Liver)
UDP glucose is the
activated form of glucose.
Outline of glycogenesis
Blood glucose

Glucose
ATP Hexokinase
ADP
G6P
PG mutase
G1P
G1P uridyl transferase
UDP Glucose
Glycogen synthase
Glycogen
 Formation of new glycogen particle

• Although glycogen synthase

can enlarge existing glycogen
particles, it cannot synthesize
new glycogen particle
because it need nonreducing
ends from existing glycogen
as primer.

Glycogen synthase makes alpha (1-4) linkage in glycogen

 Glycogen synthase
• Regulatory enzyme
• Makes alpha (1-4) linkage in glycogen
• Can not initiate chain reaction using free
glucose
• Only elongate the chain
• Therefore requires a primer to initiate the
synthesis
Glycogenin serves as primer for synthesis of
new glycogen particles
 Glycogenin itself catalyses
this reaction (enzyme)

Glucose primer

Elongation

branching
Branching by glycogen-branching enzyme

• Glycogen-branching enzyme transfer of a terminal

fragment of 6 or 7 glucose redisues from the
nonreducing end of a glycogen branch having at
least 11 residues to the C-6 hydroxyl group of a
glucose residue at a more interior position of the
same or another glycogen chain.
Every glycogen particle has a glycogenin buried
inside
 GLYCOGENOLYSIS

• Break down of glycogen into glucose

• Not a simple reversal of glycogenesis
• Stimulated by glucagon & epinephrine
• Separate cytosolic enzymes
 Glycogen Degradation

• Glycogen Phosphorylase
– Shortening of chain, cleaves α (1-4) bonds
– Hydrolyzes glucose units from glycogen
– Produces glucose-1-P
• Removal of branch points
– Debranching enzyme complex
• Glucan transferase
• Alpha-1,6-glucosidase
Glucose 6-phosphate
has 3 fates.
Glycogen phosphorylase catalyzes the breakdown of
glycogen.

Glycogen + Pi  Glucose 1- phosphate + glycogen

(n residues) (n-1 residues)
Pyridoxal phosphate is the coenzyme for phosphorylase.

(Vitamin B6)

The active site is

hydrophobic.
 Phosphorylase is specific for the α-1,4 linkage. Two
additional enzymes are required.

Non reducing end

Linear molecule
is created.

Limit dextrin
Shifts 3 glycosyl units to the core. (phosphorylase can not
Debranching degrade further)

Hydrolyzes the single Release free glucose

1,6 glucose unit to free Hexokinase →glu.6-P
glucose.
GNG Vs Glycocogenolysis
Glycogenesis Vs Glycogenolysis
 Remember!
• Liver contains glucose 6-phosphatase.
• Muscle does not have this enzyme.
WHY?
The liver releases glucose to the blood to be taken
up by brain and active muscle. The liver
regulates blood glucose levels.

The muscle retains glucose 6-phosphate to be use

for energy. Phosphorylated glucose is not
transported out of muscle cells.
 Regulation of Glycogen Metabolism

1) Hormonal
control
 Hormonal Regulation of Glycogen Synthase
Feeding
• Insulin
– Reduces [cAMP]
• Stimulates
phosphodiesterase
X
– Induces and
activates protein
phosphatase-1
• Activates GS
• Feeding results in
glycogen synthesis
√
• When blood glucose levels are high, insulin
activates protein phosphatase 1 which
stimulates glycogen synthesis.

– This is accomplished through a complex highly

regulated signal transduction pathway.

• Remember: Glycogen metabolism in liver

regulates blood glucose levels.
 Regulation of Glycogen Synthase
• Glucagon or Fasting
epinephrine
– G-protein linked
receptors
– increased [cAMP]
• cAMP activates Protein
Kinase A
• Protein kinase A
phosphorylates and
inactivates glycogen
synthase
• Little glycogen synthesis
during fasting
Regulation of Glycogen Synthase --- Fasting

b
Epinephrine and Glucagon Stimulate
Glycogen breakdown

• Muscle is responsive to epinephrine.

• Liver is responsive to glucagon and
somewhat responsive to epinephrine.
• Both signal a cascade of molecular events
leading to glycogen breakdown.
• Both utilize a G-protein-dependent
signal-transduction pathway.
 Regulation of Glycogen Phosphorylase
Fasting
• Glucagon or epinephrine
– Increase [cAMP]
– Activates Protein Kinase A
– Phosphorylates and activates
glycogen phosphorylase
• Fasting results in increased
glycogenolysis
Regulation of Glycogen Phosphorylase
Feeding

• Insulin
– Reduces [cAMP]
– Induces and activates
Protein Phosphatase-1
– Inactivates Glycogen
Phosphorylase
• Feeding results in
decreased
glycogenolysis
 2) Allosteric Regulation of
Glycogen metabolism

In muscle
• Increased glycogenolysis during
active exercise

• Increased glycogenesis during

muscle at rest
Activation of glycogen degradation by calcium

REFER
Coordinated Regulation of Glycogen
Metabolism
REFER the biochemical basis of glycogen
storage diseases
GLYCOGEN
STORAGE
DISEASES
GSD Type I: Von Gierke disease
GSD Type II: Pompe disease
GSD Type V: Mc Ardle’s disease
 A Take Home Lesson!
• Low blood glucose level = starved state;
Glucagon stimulates glycogen breakdown,
inhibits glycogen synthesis.
• High blood glucose levels = fed state; insulin
stimulates glycogen synthesis and inhibits
glycogen breakdown.