FORMATION OF GLYCOGEN (GLYCOGENSIS)

AND GLYCOGENOLYSIS

Lecture # 20
Presented by: Dr. Farzana Khan
Lecturer: Bakhtawar Amin college Pharmaceutical Sciences Multan
Reference: Pankaja Naik, Essential of Biochemistry ,1st edition. (Page No.168-173 )
U. Satyanarayana, Biochemistry ,4rth edition
(Page No. 263)
 What is glycogen?
Glycogen is the storage form of glucose in animals, as is starch in
plants.
It is stored mostly in liver (6-8%) and muscle (1-2%).
Due to more muscle mass, the quantity of glycogen in muscle(250
g) is about three times higher than that in the liver (75 g).
Glycogen is stored as granules in the cytosol, where most of the
enzymes of glycogen synthesis and breakdown are present.
 Functions of glycogen
The prime function of liver glycogen is to maintain the blood
glucose levels, particularly between meals.
Liver glycogen stores increase in a well-fed state which are depleted
during fasting.
Muscle glycogen serves as a fuel reserve for the supply of ATP
during muscle contraction.
GLYCOGENESIS

Definition
Glycogenesis is the pathway for the formation of glycogen from glucose. This
process requires energy, supplied by ATP and uridine triphosphate (UTP).

Location
It occurs in muscle and liver.
Reactions of Glycogenesis
1. Glucose is phosphorylated to glucose-6-phosphate catalyzed by
hexokinase in muscle and glucokinase in liver.
2. Glucose-6-phosphate is converted to glucose-1-phosphate by the
enzyme phosphoglucomutase.
3. Glucose-1-phosphate reacts with uridine triphosphate (UTP) to
form uridine diphosphate glucose (UDP-GIc). The reaction is
catalyzed by the enzyme UDP-glucose pyrophosphorylase.
4. By the action of the enzyme glycogen synthase, the C1 of the glucose of
UDP-Glc forms a glycosidic bond with C4 of a terminal glucose residue of
pre-existing glycogen molecule (glycogen primer), liberating uridine
diphosphate (UDP). Thus, pre-existing glycogen molecule must be present to
initiate this reaction.
5. In the above reaction, a new α-1,4 linkage is established between carbon
atom 1 of incoming glucose and carbon 4 of the terminal glucose of a
glycogen primer.
6. When the chain has been lengthened to a minimum of 11 residues, a second
enzyme, the branching enzyme, transfers a part of the 1,4-chain (minimum
length of 6-glucose residues) to a neighboring chain to form α-1,6-linkage,
thus establishing a branching point in the molecule. The branches grow by
further additions of glucose units and further branching.
Glycogenolysis
Definition and Location
Glycogenolysis is the degradation of glycogen to glucose-6-phosphate
and glucose in muscle and liver respectively. Glycogenolysis is not the
reverse of glycogenesis but is a separate pathway.
Reactions of Glycogenolysis
1. Glycogenolysis occurs primarily by phosphorolytic breaking of α-1,4-glycosidic
bonds of glycogen to yield glucose-1-phosphate and residual glycogen molecule. This
process is catalyzed by the enzyme glycogen phosphorylase. The glucose residues
from outermost chain of the glycogen molecule are removed sequentially until
approximately four glucose residues remain on either side of a branch point having α-
1,6 linkage.
2.Phosphorolysis cannot continue until the branch is removed. This is accomplished
by debranching enzyme. It has two catalytic activities—glucan transferase and 1,6-
glucosidase.
 First, it acts as a glucan transferase and transfers three of the remaining residues from
one branch to the other. This exposes the α-1,6 branch point.
 In the second step, the hydrolytic splitting of the α-1,6 linkages occurs by the action
of 1,6- glucosidase. This step releases free glucose. Further splitting of the glycogen
can then proceed by the actions of phosphorylase until another branch point is
reached. The action of glucan transferase and 1,6-glucosidase are repeated.
The combined action of phosphorylase and debranching enzyme leads to the complete
breakdown of glycogen with the formation of glucose-1- phosphate and free glucose
(from hydrolytic cleavage of the 1,6-glycosidic bond).
3. Next, glucose-1-phosphate is converted to glucose 6-phosphate by
phosphoglucomutase. This is a reversible reaction.
4. In the liver but not in the muscle, there is a specific enzyme, glucose-6-phosphatase,
that cleaves glucose 6-phosphate to glucose and diffuse from the hepatic cell into the
blood. As glucose-6-phosphatase is absent in muscle, free glucose cannot be produced
from glucose-6-phosphate in muscle. Moreover, glucose-6- phosphate cannot diffuse out
of the muscles. Therefore, muscle cannot provide glucose to maintain blood glucose
level.
Pathway of glycogenesis and glycogenolysis in liver where, UTP = Uridine triphosphate,
UDP = Uridine diphosphate, UDPGIc = Uridine diphosphate glucose
 Regulation of Glycogenesis and Glycogenolysis
The principal enzymes controlling glycogen metabolism are glycogen
phosphorylase and glycogen synthase which are regulated reciprocally.
Regulation of these enzymes involve:
• Hormonal regulation
• Allosteric regulation.
1. Hormonal Regulation
Epinephrine and glucagon regulate glycogen breakdown and glycogen
synthesis.
Epinephrine (in liver and muscle) and glucagon (in liver) stimulates glycogen
breakdown (glycogenolysis) and inhibits glycogen synthesis (glycogenesis).
 Regulation of glycogenesis
Glycogen synthase is the regulatory enzyme of glycogenesis. It exists in two forms:
 Glycogen synthase-a, an active or dephosphorylated form
 Glycogen synthase-b, an inactive or phosphorylated form.
Glucagon in liver and epinephrine in liver and muscle activates adenylate cyclase
enzyme that catalyzes the synthesis of c-AMP. c-AMP in turn activates c-AMP
dependent protein kinase.

c-AMP dependent protein kinase then phosphorylates glycogen synthase and thereby
inactivates glycogen synthase and synthesis of glycogen is inhibited.
The hormone insulin increases the phosphodiesterase activity in liver and lowers the
c-AMP levels and inhibits the action of glucagon and epinephrine.
Hormonal regulation of glycogenesis
 Regulation of glycogenolysis
Glycogen phosphorylase is the regulatory enzyme of glycogenolysis. It exists in two
forms:
 Glycogen phosphorylase-a, an active or phosphorylated form
 Glycogen phosphorylase-b, an inactive or dephosphorylated form.
Degradation of glycogen is stimulated by epinephrine in the muscle and by glucagon
in the liver via activation of adenylate cyclase that catalyzes the synthesis of c-AMP.
The consequent increase in levels of c-AMP in turn activates c-AMP dependent
protein kinase. Active c-AMP dependant protein kinase phosphorylates the inactive
form of phosphorylase kinase to its active form.
Active phosphorylase kinase eventually activates inactive form of glycogen
phosphorylase to its active form. Active form of glycogen phosphorylase stimulates
breakdown of glycogen to glucose-1-P
Hormonal regulation of glycogenolysis
 Allosteric Regulation
Glycogen synthase is allosterically activated by glucose-6-phosphate when it is
present in elevated concentrations.

In contrast, glycogen phosphorylase is allosterically inhibited by glucose-6-

phosphate.

The Ca2+ ions stimulate the glycogenolysis by activation of glycogen

phosphorylase.
Increased level of AMP in vigorously contracting muscles stimulates glycogen
breakdown by stimulating glycogen phosphorylase allosterically. However, in
resting muscles ATP inhibits the glycogen breakdown by allosteric inactivation
of glycogen phosphorylase.
Allosteric regulation of glycogenesis and glycogenolysis
 Significance of Glycogenolysis and Glycogenesis
The functional role of glycogen differs considerably from tissue to tissue, as we can
see in the case of liver and muscle.
In liver
Following a meal, excess glucose is removed from the portal circulation and stored as
glycogen by glycogenesis. Conversely, between meals, blood glucose levels are
maintained within the normal range by release of glucose from liver glycogen by
glycogenolysis.
In muscle
The function of muscle glycogen is to act as a readily available source of glucose
within the muscle itself during muscle contraction. The muscle cannot release glucose
into the blood, because of the absence of glucose-6-phosphatase that hydrolyzes
glucose 6-phosphate to glucose. Therefore, muscle glycogen stores are used
exclusively by muscle.
Reference:
Pankaja Naik, Essential of Biochemistry ,1st edition.
U. Satyanarayana, Biochemistry ,4rth edition.