Introduction

All the human cells require a constant supply of glucose for proper functioning. Glucose is used as an energy source in most of the cells. It is essential for the normal functioning of brain cells, red blood cells, and skeletal muscles. Blood glucose is mainly obtained from three sources; diet, gluconeogenesis, and glycogen degradation. 

Glycogen is a macromolecule belonging to the category of polysaccharides. It is the only glucose storage molecule found in animal cells. Glycogen can be synthesized in certain animal cells by the process of glycogenesis. In this article, we study in detail the structure, properties, synthesis, metabolism, and importance of glycogen. So, keep reading. 

Structure

Glycogen is a polymer of alpha-D-glucose. Thousands of glucose molecules in glycogen are linked together via alpha 1-4 and alpha 1-6 glycosidic linkages. Glycogen is made up of long chains of glucose molecules that show abundant branching. 

All the glucose molecules in the linear chain of glycogen are linked via alpha 1-4 glycosidic bonds. Branches arise from this linear chain via an alpha 1-6 glycosidic bond. It means that the glucose molecule at the branch point is attached to the main chain via alpha 1-6 bond. The rest of the glucose molecules in the branch have alpha 1-4 linkages.

Branching takes place at an interval of 8 to 12 glucose subunits. 

Glycogen molecule also has a protein at its center known as glycogenin protein. This protein forms the core of the glycogen molecule. 

Glycogen molecule organizes itself in a spherical form around the glycogen in protein in such a way that the whole structure looks like a tree with the branches arising from the center. 

In the cytoplasm of living cells, glycogen is present in the form of granules. These granules are formed by glycogen with water present in the cytoplasm. 

Synthesis

Glycogen is synthesized majorly in the liver and muscle cells by a process known as glycogenesis. This process takes place in the cytosol and uses energy in the form of ATP and UTP. 

Glycogenesis is the process in which glycogen molecules are synthesized from glucose monomers. These glucose monomers are joined via glycosidic bonds to form a linear chain. Later, branches are formed. Thus, glycogenesis involves two steps;

• Synthesis of linear glycogen chain
• Formation of branches

Synthesis of linear glycogen chain

The linear chain of glycogen is made by joining together the UDP-glucose molecules. It involves the following steps;

1. Synthesis of UDP-Glucose

Uridine diphosphate glucose (UDP-Glucose) acts as the precursor of all glucose molecules found in glycogen. It is synthesized from a  molecule of glucose-1-phosphate and UTP by UDP-glucose pyrophosphorylase enzyme. A molecule of pyrophosphate (PP_i) is also generated in this process.

The glucose-1-phosphate molecule used in this reaction is made from glucose-6-phosphate by phosphoglucomutase enzyme. This enzyme transfers the phosphate group from the last carbon to the first carbon of glucose. 

2. Synthesis of a primer

In the next step, a primer is created in the form of glycogenin protein. It is necessary because glycogen synthase enzyme can only attach glucose molecules to an already existing primer which could be an already existing fragment of glycogen or the glycogenin protein. 

Glycogenin protein has tyrosine amino acids. The hydroxyl group present in the sidechain of tyrosine acts as an acceptor of the first glucose molecule. The process is catalyzed by the glycogenin protein itself. 

3. Elongation of glycogen chain

Once the primer has been constructed, the linear glycogen chain is constructed by joining the glucose molecules via alpha 1-4 glycosidic bonds. It involves the transfer of glucose molecule from UDP-glucose to the non-reducing end of the glycogen chain. The non-reducing end of the glycogen chain is the one having terminal sugar with no free functional group. The anomeric carbon of terminal sugar is linked to another glucose via glycosidic bond. 

This entire process is catalyzed by the glycogen synthase enzyme. The UDP molecules released in this process are reconverted to UTP by nucleoside diphosphate kinase enzyme.

Formation of Branches

The molecule resulted from the above steps is a polymer of glucose subunits linked in a linear chain. Such a molecule is found in plants and is called amylose. 

In humans and other animals, this linear molecule undergoes extensive tree-like branching to form glycogen.

The branches in glycogen are formed by a special enzyme called amylo-alpha(1-4)->alpha(1-6)-transglucosidase. This enzyme has two activities;

• Alpha 1-4 glucosidase activity
• Alpha 1-6 glucosidic activity

The process of branching involves two steps;

• In the first step, the branching enzyme removes a fragment containing six to eight glucosyl residues from the non-reducing end of the glycogen chain. This process involves the hydrolysis of an alpha 1-4 glycosidic bond.  
• In the next step, the above fragment is attached to a non-reducing glucosyl residue by forming an alpha 1-6 glycosidic bond. 

As a result of this process, two non-reducing ends are formed. The elongation of the chain continues at both these ends. After elongation, additional branches are created by the same process. 

The process repeats several times and a molecule of glycogen is formed having abundant tree-like branches originating from the central core protein, glycogenin.

Occurrence

Glycogen is only found in animals. In humans, it is mainly found in liver and skeletal muscles in large amounts. Other cells of the body also contains glycogen in small amounts for their own uses. 

In a normal person, 400 grams of glycogen is present in skeletal muscles making 1-2% of the resting muscle mass. The liver of a well-fed man contains around 100 grams of glycogen that makes around 10% of its weight.

The glycogen stores present in liver fluctuate with the blood glucose levels. Its amount increases in well-fed state and depletes during fasting.  On the other hand, the glycogen stores in muscles are almost constant. They only undergo little changes in the case of strenuous exercise and are not affected by fasting. However, starvation depletes glycogen stores of both liver and skeletal muscles. 

Glycogenolysis

The glycogen present in animal tissues is broken down to release glucose molecules in the process of glycogenolysis. This degrative pathway is not simply a reversal of glycogenesis, the glycogen synthetic reactions. In this pathway, different enzymes are required. 

The process of glycogenolysis takes place in the cytosol of cells having glycogen stores. It involves two steps; 

• Shortening of chain
• Removal of branches

Each of these two processes require different type of enzymes. 

Shortening of chain

This involves the breaking of alpha 1-4 glycosidic bonds between the glucose residues present in glycogen. This reaction is carried out by glycogen phosphorylase enzyme. 

This enzyme cleaves the glucose residues from the non-reducing end of the glycogen chain and releases them as glucose-1-phosphate molecules. 

The process continues until 4 glucose subunits remain at the end of the chain before a branch point. 

The structure thus formed having four glucose residues before the branch point is called limit dextrin. 

This limit dextrin is further degraded after the process of debranching. 

Removal of branches

The debranching process is carried out by a special enzyme called the glycogen debranching enzyme. 

This enzyme has two activities;

• Oligo alpha(1-4) to alpha(1-4) glucantranferase activity
• Amylo alpha(1-6) glucosidase activity

Corresponding to the double activity of the enzyme, the debranching process involves two steps;

• In the first step, the enzyme removes the last three of the four glucosyl residues at a branch and transfers them to the non-reducing end of another branch, lengthening the chain. This chain is again cleaved by the glycogen phosphorylase enzyme until the four residues remain, and the process is repeated.
• In the second step, the enzyme cleaves the alpha 1-6 glycosidic bond at the branch point of glycogen and releases free glucose molecule. 

In the process of glycogenolysis, two products are formed;

• Glucose-1-phosphate
• Glucose

The glucose-1-phosphate molecule is the major product of glycogenolysis. Unless it is converted to glucose-6-phosphate, it cannot be used in the glycolytic pathways to obtain energy. This conversion is carried out by phosphoglucomutase enzyme. 

In the liver cells, this glucose-6-phosphate molecule is transferred to the ER where the phosphatase enzyme cleaves it into glucose. The glucose thus formed is released into the cytosol. In the liver, glucose molecules obtained by degradation of glycogen are released into the blood. 

The skeletal muscles lack the glucose-6-phosphatase enzyme. They cannot generate free glucose from glycogen and thus, are not sources of free glucose.

Lysosomal degradation

A small fraction of glycogen is continuously degraded by the lysosomal enzyme alpha 1-4 glucosidase. This degradation releases free glucose molecules from glycogen. Although the importance of this pathway is not known, the absence of it can result in one of the several glycogen storage diseases. 

Clinical Importance

Glycogen is the most important energy reserve in our body. It provides glucose to our body in times of fasting. Any abnormality in the synthesis or degradation of glycogen can result in different metabolic conditions. 

Any defect in the process of glycogen degradation results in its abnormal accumulation inside the cells. These metabolic defects are collectively known as glycogen storage diseases. All these are hereditary disorders in which one or more enzymes of glycogen metabolism are deficient or absent. Some of these storage diseases are discussed below.

Von Gierke Disease

It is also known as glycogen storage disease type 1a. in this disease, glucose-6-phosphatase enzyme is deficient. As a result, free glucose molecules cannot be generated from glycogen by the liver and cannot be released into the blood. 

The glucose demand of body cannot be fulfilled in times of fasting. Thus, it results in fasting hypoglycemia. 

It affects both liver and kidneys resulting in progressive hepatomegaly, splenomegaly, and renal disease. Growth retardation and delayed puberty are also seen in the affected people. 

It is the most severe glycogen storage disease that also results in lactic acidemia, hyperlipidemia, and hyperuricemia. 

Glucose-6-phosphate translocase deficiency

As the name indicates, the glucose-6-phosphate translocase enzyme is deficient in this disease. The other name of this disease is glycogen storage disease type 1b. 

The signs and symptoms of this disease are similar to that of Von Gierke disease. Besides, neutropenia and recurrent infections are also seen in this metabolic disorder. 

Pompe Disease

It is a lysosomal storage disease. In this disorder, the lysosomal alpha 1-4 glucosidase enzyme is deficient. Although it is a generalized disease, it primarily affects the heart, liver, and muscle. 

Excessive abnormal glycogen storage vacuoles can be seen in lysosomes in this disease. Although the blood glucose levels are normal, it results in massive cardiomegaly. Usually, death results in an early age due to heart failure. 

Cori Disease

It is type 3 glycogen storage disease characterized by deficiency of debranching enzyme. Glycogen with abnormal structure is found in cells in this disease. It can result in fasting hypoglycemia. 

McArdle Syndrome

It is type 5 glycogen storage disease with deficient glycogen myophosphorylase enzyme. Only skeletal muscles are affected. It is characterized by temporary weakness and cramping of skeletal muscle after exercise. 

Muscle development is normal in such individuals. However, myoglobinuria and myoglobinemia is sometimes seen in such patients. 

Summary

Glycogen is an extensively branched polymer of glucose found only in animals.

It is made up of alpha-D-glucose subunits attached via 1-4 glycosidic bonds. Alpha 1-6 glycosidic linkage is seen at the branch points. 

Glycogen molecule shows abundant tree-like branching originating from a central core that contains a protein called glycogenin. 

The synthesis of glycogen takes place in the cytosol. It involves the following steps;  

• Synthesis of UDP-glucose that provides all glucose residues in glycogen
• Synthesis of a primer on which the glycogen chain is constructed
• Elongation of glycogen chain
• Formation of branches

Glycogen is abundantly present in the liver and skeletal muscles of animals. Glycogen stores of the liver release glucose into the blood during fasting. 

Glycogen is metabolized in the human body by the process of glycogenolysis. It takes place in two steps;

• Shortening of the chain 
• Removal of branches

The product of glycogenolysis are glucose-1-phosphate and glucose. In the liver, glucose-1-phosphate is converted to glucose and released into the blood. 

Any abnormality in the degrative pathway of glycogen results in abnormal glycogen accumulation within the cells. These disorders are collectively known as glycogen storage diseases. 

Some of the diseases discussed in this article are;

• Von Gierke disease
• Glucose-6-phosphate translocase deficiency
• Pompe disease
• Cori disease
• McArdle disease

Frequently Asked Questions

What is glycogen?

Glycogen is a polymer of glucose molecules found only in animals. It is a storage polysaccharide that is made up of glucose molecules. 

Where is glycogen found?

Glycogen is mainly found in the liver and muscle cells of animal cells. Its major stores are present in the liver. 

How glycogen is broken down?

Glycogen is broken down in the liver by glycogen phosphorylase enzyme. This enzyme breaks glycogen into phosphorylated glucose molecules. The glucose phosphatase enzyme releases free glucose molecules to be used by cells. 

What is the importance of glycogen?

Glycogen is a storage carbohydrate found in animal cells. Glucose in animals is stored in the form of glycogen. 

References

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2. Guyton, Arthur C.; John Edward Hall (2011). Guyton and Hall Textbook of Medical Physiology. New York, New York: Saunders/Elsevier. ISBN 978-5-98657-013-6.
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6. https://upload.wikimedia.org/wikipedia/commons/9/9f/2nd_step_of_glycogenolysis.png