Glycogen metabolism Pathways and glycogen storage diseases (GSD)

Glycogen metabolism pathways

In mammals, glycogen serves as a source of stored carbohydrates. A homopolysaccharide, it is branched. Glucose is the monomer of glycogen. For a short period, glycogen acts as a source of energy and we can consider it our currency kept in a locker, while fatty acids are our currency kept in a bank since they function as a source of energy for longer periods. As a species, we must rely on glucose to provide our energy requirements. This is the amount of glycogen we can store, and if it drops, glycogen breakdown takes place, and if too many carbohydrates are in our blood, glycogen synthesis takes place.

As a result, fat only breaks down after glycogen is depleted. The glycogen in our body helps to maintain blood glucose homeostasis or the amount of glucose in our blood. As glycogen contains so many reducing ends, it helps to break down glycogen as it contains several branches. Due to the presence of several non-reducing ends, the process of glycogen breakdown and synthesis becomes fast. As glycogen is a branched carbohydrate, it can occupy a large number of spaces, yet we can only store very few glycogen molecules at a time. About fat molecules, therefore, there is a limited amount of glycogen that can be stored in the body.

Additionally, glycogen cannot be stored without water. The muscles and liver are the sites of glycogen storage. When glycogen is synthesized from glucose molecules, it is known as glycogenolysis, while when glycogen is broken down, it is known as glycogenolysis. Combined glycogenolysis and glycogenesis make up glycogen metabolism.

Seven steps constitute glycogen synthesis:

• Glucose is converted into glucose 6 phosphate in the first step. Hexokinase consists of several different isozymes. Among the three kinds of hexokinases, I, II, and IV are found in muscle and liver, respectively. ATP is utilized during this process. There may be more than one fate for glucose 6 phosphates.
• A chemical reaction occurs between glucose 6 phosphate and glucose 1 phosphate via phosphoglucomutase. Glucose 1 phosphate precedes the formation of glycogen. The production of glycogen occurs when glucose 6 phosphates are converted to glucose 1 phosphate. This step is considered to be very important in glycogenesis.
• With the help of the enzyme UDP Glucose phosphorylase, glucose 1 phosphate later converts into UDP-glucose. Each glucose molecule is used as one UTP. Therefore, we can say that the glycogen synthesis process is relatively expensive.

This process is irreversible because of nucleotide-glucose formation. As a result, Inorganic Pyrophosphate (PPi) is removed, and this is a highly energetic process. There is a Δ G0 of -19.2 KJ/mol for this reaction. Nucleotide integration into glucose molecules provides several benefits, including that it forces the reaction forward. Nucleotides sugar is an excellent living group since they promote a nucleophilic attack on sugar carbon, and the nucleotide group cell can set aside a pool of hexose for glycogen synthesis by tagging them with this molecule.

• The main enzyme that is involved in glycogen synthesis is called glycogen synthase but it comes with some disadvantages. De-novo glycogen synthesis is not possible, so it cannot begin from scratch. Another enzyme functions as a primer and extends the chain at the start of the reaction. Glycogen is this enzyme.

The glycogen in acts as both a primer as well as a base on which glycogen synthesis begins and is extended. It adds glucose to its Tyrosine Residue (number 194) by converting one UDP-Glucose to glucose. Up to eight glucose molecules are transferred from UDP - Glucose to the first glucose molecule in the following step.

• Initial glycogen chains contain eight glucose residues. At that point, it is transferred to Glycogen Synthase, the main enzyme responsible for glycogen synthesis. By now, the glycogen synthase has transferred a few glucose molecules from UDP-glucose to the non-reducing end of a molecule of glycogen.
• This process also involves the enzyme known as the glycogen branching enzyme. Transglucosylase or Glycosyl (4→ 6) transferase is also known as Amylo α (1→ 4) to α (1→ 6). Transfer of 6 to 7 glucose residues from the non-reducing end of glycogen containing at least 11 residues is performed by this enzyme. A new branch is made when a α (1→4) bond is broken and transferred at a α (1→6) hydroxyl group of a glucose residue.
• Furthermore, glycogen synthase does add up glucose residue on both ends of the chain, namely on the main chain, as well as on the branch chain. It is possible to create another branch in either the main chain or in the pre-existing branch after some time. It is thought that branching is a biological process for making glycogen molecules more soluble and increasing the number of nonreducible ends, so that the rate of glycogen synthesis and breakdown may be accelerated.

Glycogen storage disease (GSD)

Glucose is the main source of the energy for the body and through the action of enzymes, the body just stored the glucose in the form of glycogen which is then released into the blood whenever the body needs it. GSD exists in many types, but all people who have the condition were born with it. Symptoms of GSD include:

• Because of a lack of enzymes, the liver is unable to control glucose and glycogen use, as glucose cannot be turned into glycogen or released from glycogen.
• Hepatic glycogen storage is abnormally high.
• Hypoglycemia is a condition in which there is not enough glucose in the blood.

Sugars offer energy to the body and hence sugars as well as glucose is found in foods. The blood sugar level increases after food consumption. Glycogen is therefore not needed immediately for the body and hence it is the storage form of glucose. Eventually, the body will use this stored energy as the levels of blood glucose begin to drop. For sugars to work in the body, enzymes need to process them, which is why glycogen is stored as a form of storage. A liver can accumulate glycogen or one of its related starches if the enzymes required to process them are not present.
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Types

The number of GSD types is at least ten. The types are grouped by the missing enzyme. Type I, III, and IV of GSD are the most common forms. There is about one type of GSD out of every 20,000 people.

Von Gierke disease (GSD I) - Glucose-6-Phosphatase deficiency leads to this condition.

Cori disease (GSD II) - A debrancher enzyme deficiency causes this condition. This leads to an abnormal structure of glycogen molecules within the body, which interferes with the breakdown of glycogen into free glucose.

Amylopectinosis (GSD IV) - There is no increase in glycogen concentration in the tissues. It is the outer branches of glycogen that accumulate in the tissues that are very long. There is no branching enzyme present in this type of GSD. It is believed that abnormal glycogen stimulates the immune system. Cirrhosis is a condition in which the liver and other organs, such as muscles and the heart, shiver or act like scarred.

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