TERM PAPER

TITLE: The metabolism of Glycogen in Animals

SUBMITTED BY: SAHIR KUMAR PRADHAN

REGISTRATION NO.: 23mscbot02

COURSE TITLE: GENERAL BIOCHEMISTRY

Course code: BOT.506

M.Sc. BOTANY 1st Semester

SUBMITTED TO: DR. VINAY KUMAR

DEPARTMENT OF BOTANY

CENTRAL UNIVERSITY OF PUNJAB, BATHINDA

 The metabolism of Glycogen in Animals
Glycogen is a large, branched polysaccharide that is the main storage form of glucose in
animals and humans1. It is composed of many glucose units linked by α-1,4 glycosidic bonds,
with branches formed by α-1,6 glycosidic bonds. Glycogen has a helical structure and forms
granules in the cytoplasm of liver and muscle cells1. Glycogen is synthesized from glucose
when blood glucose levels are high and is broken down to glucose when blood glucose levels
are low. Glycogen serves as a ready source of glucose for tissues throughout the body,
especially the brain and muscles.
Glycogen has the following features: -
• Glycogen makes up 6-10% of the liver by weight and 1-2% of muscle by weight.
• Glycogen granules have many tiers of branched chains of D-glucose, with each chain
containing 12 to 14 glucose residues.
• Glycogen synthesis and breakdown are catalyzed by glycogen synthase and glycogen
phosphorylase, respectively.
• Glycogen metabolism is regulated by hormones such as insulin, glucagon, cortisol,
epinephrine, and norepinephrine, as well as by allosteric effectors such as glucose,
glucose-6-phosphate, ATP, and AMP.
• Glycogenin, a protein that initiates glycogen synthesis, is located at the core of each
glycogen granule.

Fig. 1. Structure of a small part of Glycogen showing branch point and glycosidic bonds

Difference between Glycogen and starch

Glycogen and starch are both complex carbohydrates that store glucose, but they have some
differences in their structure and function. Here are some of the main differences: -
• Glycogen is the storage form of glucose in animals and fungi, while starch is the
storage form of glucose in plants.
• Glycogen is made up of one type of polymer, while starch is made up of two types
of polymers: amylose and amylopectin.
 • Glycogen has more branches than starch, which makes it more compact and soluble.
• Glycogen is mainly found in the liver and muscles of animals, where it provides a
quick source of energy when needed. Starch is mainly found in seeds, roots, and
tubers of plants, where it serves as a long-term energy reserve.
• Glycogen is the storage form of glucose in animals and fungi, while starch is the
storage form of glucose in plants.
• Glycogen is made up of one type of polymer, while starch is made up of two types
of polymers: amylose and amylopectin.
• Glycogen has more branches than starch, which makes it more compact and soluble.
• Glycogen is mainly found in the liver and muscles of animals, where it provides a
quick source of energy when needed. Starch is mainly found in seeds, roots, and
tubers of plants, where it serves as a long-term energy reserve.

Glycogenolysis: -
Glycogenolysis is the process of breaking down glycogen, a complex carbohydrate stored in
the liver and muscles, into glucose-1-phosphate, which can be converted into glucose-6-
phosphate and used for energy production or blood glucose maintenance. The breakdown
process involves three enzymes:
• Glycogen phosphorylase: This enzyme cuts off glucose molecules from the
ends of the glycogen chains by adding a phosphate group to them. This is
different from how amylase breaks down starch in the digestive system, where
water is added instead of phosphate. The phosphate group helps to preserve
some of the energy in the glucose molecule. The enzyme needs another
molecule called pyridoxal phosphate to help it do this. Pyridoxal phosphate is
usually involved in amino acid metabolism, but here it acts as an acid to make
the phosphate attack the glucose bond.

Fig. 2. Removal of a glucose residue from the nonreducing end of a glycogen chain by glycogen phosphorylase
 • Glycogen debranching enzyme: This enzyme deals with the branches in the
glycogen structure, where glucose molecules are linked differently. It moves
some of the glucose molecules from the main chain to the branch point, creating
a new end for the glycogen phosphorylase to work on. It also removes the last
glucose molecule at the branch point by adding water to it, producing free
glucose.
• Glycogen debranching enzyme: This enzyme deals with the branches in the
glycogen structure, where glucose molecules are linked differently. It moves
some of the glucose molecules from the main chain to the branch point, creating
a new end for the glycogen phosphorylase to work on. It also removes the last
glucose molecule at the branch point by adding water to it, producing free
glucose.

Fig. 3. Glycogen breakdown near an (α1→6) branch point.

Glucose 1-Phosphate Can Enter Glycolysis or, in Liver, replenish Blood Glucose
Glucose 1-phosphate, the end product of the glycogen phosphorylase reaction is
converted to glucose 6-phosphate by phosphoglucomutase. This enzyme shifts the
position of the phosphate group on the glucose-1-phosphate molecule, making it
glucose-6-phosphate. The enzyme has a phosphate group attached to a Serine (S)
residue, which it transfers to the glucose molecule, and then receives back from
another position. The reaction is as follows:
Glucose 1-phosphate ↔ glucose 6-phosphate
The glucose-6-phosphate molecule can then be used for different purposes in different tissues:
• In skeletal muscle: It can enter the glycolysis pathway, where it is broken down further
to produce energy (ATP) for muscle contraction.
• In liver: It can be converted back to glucose, which can be released into the blood to
maintain blood glucose levels.
• In muscle and adipose tissue: These tissues do not have the glucose-6-phosphatase
enzyme, so they cannot convert the glucose-6-phosphate molecule back to glucose.
Therefore, they do not contribute to the blood glucose levels, but use the glucose-6-
phosphate molecule for their own energy needs.

Fig. 4. Reaction catalyzed by phosphoglucomutase. In step 1, the enzyme donates its phosphoryl group (blue)
to glucose 1-phosphate, producing glucose 1,6-bisphosphate. In step 2, the phosphoryl group at C-1 of glucose
1,6-bisphosphate (red) is transferred back to the enzyme, reforming the phosphoenzyme and producing
glucose 6-phosphate.

Glucose 6 phosphate is dephosphorylated in the liver for transport out of the liver
Glucose-6-phosphatase enzyme removes the phosphate group from the glucose-6-phosphate
molecule, producing free glucose. The enzyme is located inside the endoplasmic reticulum
(ER), a membrane-bound organelle in the cell. The glucose-6-phosphate molecule is
transported from the cytoplasm (the main part of the cell) to the ER by a transporter protein
(T1). The glucose-6-phosphatase enzyme then hydrolyzes the glucose-6-phosphate molecule,
releasing glucose and phosphate. The glucose and phosphate are then transported back to the
cytoplasm by two other transporter proteins (T2 and T3). The glucose then exits the liver cell
through another transporter protein (GLUT2) on the plasma membrane (the outer layer of the
cell). By having the glucose-6-phosphatase enzyme inside the ER, the liver cell prevents the
glucose-6-phosphate molecule from entering the glycolysis pathway, which would use up the
glucose instead of releasing it. Some people have genetic defects in the glucose-6-
phosphatase enzyme or the T1 transporter protein, which cause a disorder called type Ia
glycogen storage disease. This disorder prevents the liver from releasing glucose into the
blood, leading to low blood sugar levels and excess glycogen accumulation in the liver.
Fig. 5. Hydrolysis of glucose 6-phosphate by glucose 6-phosphatase of the ER.

The Sugar Nucleotide UDP-Glucose Donates Glucose for Glycogen Synthesis

Sugar nucleotides, which are molecules that have a sugar and a nucleotide attached together,
are involved in many reactions that change or link sugars together. Sugar nucleotides have a
special carbon atom (called anomeric carbon) that can easily react with other molecules. Sugar
nucleotides can donate their sugar part to other sugars, forming larger molecules like
disaccharides (two sugars), glycogen (many sugars in a branched chain), starch (many sugars
in a straight or slightly branched chain), cellulose (many sugars in a straight chain), and other
complex polysaccharides (many sugars in various shapes and structures). Sugar nucleotides
can also help make different kinds of sugars, such as aminohexoses (sugars with an amino
group) and deoxyhexoses (sugars with one less oxygen atom). Sugar nucleotides can also help
make vitamin C, which is an important molecule for human health. The importance of sugar
nucleotides in making glycogen and other carbohydrate molecules was first discovered by Luis
Leloir, a scientist from Argentina, in 1953.

Fig. 6. Sugar Nucleotide

Suitability of sugar nucleotides for biosynthesis reaction

1. The formation of sugar nucleotides is a way of making the synthesis of glycosylated

products irreversible. This is because the reaction that produces a sugar nucleotide
from a nucleoside triphosphate and a hexose 1-phosphate has a small positive free-
energy change, meaning that it is slightly unfavorable. However, the reaction also
releases pyrophosphate (PPi), which is quickly broken down by an enzyme called
inorganic pyrophosphatase. This breakdown is very favorable, meaning that it releases
a lot of energy. By doing this, the concentration of PPi in the cell is kept low, which
makes the formation of sugar nucleotides more favorable. This is a common strategy in
biological polymerization reactions, where the removal of a by-product drives the
synthesis of a larger molecule.
2. The nucleotide part of the sugar nucleotide does not directly participate in the
chemical transformations of the sugar part, but it helps to bind the sugar
nucleotide to the enzyme that catalyzes the reaction. This binding increases the free
energy of the enzyme-substrate complex, which lowers the activation energy of the
reaction. This means that the reaction can proceed faster and more efficiently. The
nucleotide part also provides specificity, meaning that it ensures that only the correct
sugar nucleotide is used for a given reaction.
3. The nucleotidyl group, such as UMP or AMP, is a good leaving group, meaning
that it can easily detach from the sugar part when a nucleophilic attack occurs. A
nucleophilic attack is when a molecule or an ion with a negative charge or a lone pair
of electrons attacks a molecule or an ion with a positive charge or a partial positive
charge. The nucleotidyl group activates the sugar carbon to which it is attached, making
it more susceptible to nucleophilic attack. This is how the sugar part is transferred from
the sugar nucleotide to the acceptor molecule, such as a protein, a lipid, or another sugar.
4. The tagging of some hexoses with nucleotidyl groups allows the cell to separate
them from other hexose phosphates that have different functions. For example,
glucose 1-phosphate can be converted to UDP-glucose, which is used for glycogen
synthesis, while glucose 6-phosphate can be used for glycolysis or the pentose
phosphate pathway. This way, the cell can regulate the flux of hexoses into different
metabolic pathways.

Fig. 7. Formation of a sugar nucleotide.

Glycogenesis: -
Glycogenesis is the process of producing glycogen from glucose, a simple cellular sugar.
Glycogen is a complex carbohydrate that can be stored in the liver and muscle cells for later
use. Glycogenesis occurs when the blood glucose level is high, such as after a meal, or when
the body is in a rest period.
Glucose 6-phosphate is the starting material for making glycogen. It can come from free
glucose in the blood or from lactate produced by other cells. Glucose 6-phosphate is converted
to glucose 1-phosphate by an enzyme called phosphoglucomutase. This is a reversible
reaction that involves shifting the phosphate group from the 6th to the 1st carbon of glucose.
Glucose 1-phosphate is then combined with a nucleotide called UTP by an enzyme called
UDP-glucose pyrophosphorylase. This produces UDP-glucose and pyrophosphate.
Pyrophosphate is quickly broken down into two phosphate molecules by another enzyme
called inorganic pyrophosphatase. This makes the reaction irreversible and drives it forward.
UDP-glucose is the building block for glycogen. It is added to the end of a glycogen chain
by an enzyme called glycogen synthase. This forms a bond between the 1st carbon of UDP-
glucose and the 4th carbon of the last glucose unit on the chain. This is called an α1→4 bond.
UDP is released as a byproduct.

Fig. 8. Glycogen synthesis

Glycogen synthase can only make α1→4 bond, but glycogen also has branches that are formed
by α1→6 bond. These are made by an enzyme called glycogen-branching enzyme, which
transfers a segment of 6 or 7 glucose units from the end of a chain to an internal position on
the same or another chain. This creates a new branch point with an α1→6 bond. Branching
makes glycogen more soluble and increases the number of ends that can be accessed by
enzymes that break down or build up glycogen. These enzymes are called glycogen
phosphorylase and glycogen synthase, respectively. They only work on the ends of the chains,
not the branch points.
 Fig. 9. Branch synthesis in glycogen

Glycogenin starts a new glycogen chain

Glycogen synthase is an enzyme that can add glucose units to an existing glycogen chain, but
it cannot start a new chain from scratch. It needs a primer, which is a short chain of glucose
units, to begin synthesis. Glycogenin is a protein that can act as both a primer and an
enzyme. It can attach a glucose unit from UDP-glucose to itself, and then add seven more
glucose units to form a primer. This is called autocatalysis, because it catalyzes its own growth.
Glycogen synthase can then take over and extend the primer into a longer glycogen chain.
Glycogenin stays attached to the end of the chain, hidden inside the glycogen molecule. If
glycogenin is not working properly due to a mutation, it can cause problems in the body. For
example, it can lead to muscle weakness and fatigue, low glycogen levels in the liver, and
abnormal heart rhythms.

Fig. 10. Glycogen act as primer and enzyme.