Glycogen Metabolism: Glycogenesis, Glycogenolysis, and its Regulation

 

Glycogen Metabolism

Glycogen Metabolism- This article is all about the different aspects of glycogen metabolism: glycogenesis, glycogenolysis, and their regulation. Glycogenesis is the synthesis of glycogen from glucose. But Glycogenolysis is the dissolution of glycogen into glucose that occurs in muscles and the liver. Hormonal regulation, Allosteric regulation, and Role of Calcium in glycogenolysis regulate the Glycogen Metabolism.

What is Glycogen?

 Glycogen is a homopolymer of glucose, composed of alpha-1,4-glycosidic linkage in a linear chain, while alpha-1,6-glycosidic linkage in branched-chain. In Animals, the storage form of glucose is glycogen, as starch in animals. The liver stores 6-8% of glycogen, while 1-2% is in muscles.

Functions of Glycogen

      The prime function of liver glycogen is to maintain the blood glucose level. The glycogen stored in the liver is useful during meal times. The glycogen level of the liver depletes after 12-18 hours of a meal. And glucose will be provided by the glycogen of muscles in the form of Glucose-6-phosphate because the enzyme glucose-6-phosphatase is absent in muscles. The glycogen stored in the muscles provides ATP energy during muscle contraction.

Why Stored-glycogen serves as a fuel reserve?

     Stored-glycogen serves as fuel during routine and day-by-day works because of the following reasons:

• Transportation of Glycogen is rapid in the body, but Fat mobilization is slow.
• Glycogen generates energy in the absence of O2, but fat needs O2 to generate energy.
• The brain needs a continuous supply of glucose. And glycogen completes its need.
• Fat is like a fixed deposit, but glycogen is a current or saving account in the bank.

Glycogenesis (Synthesis of Glycogen)

     Glycogenesis is the synthesis of glycogen (homopolymer molecule of glucose) from glucose. The site for glycogenesis is Cytosol in the Liver and Muscles. Following are the different steps of Glycogenesis:

1) Activation of Glucose: 

     In the first step of glycogenesis, glucose activation takes place. The enzymes hexokinase (in muscles) and glucokinase (in the liver) acts on glucose and convert it into Glucose-6-phosphate. Then Phosphoglucomutase converts Glucose-6-phosphate to Glucose-1-phosphate. Then, UDP-glucose-phosphorylase synthesizes Uridine diphosphate (UDP) from Glucose-1-phosphate and UTP.

2) Initiation of Glycogenesis:

     The next step is the initiation of glycogenesis, which is done through a glycogen primer that attaches glucose of UDP-glucose. But recently it is found that in the absence of glycogen primer, a specific protein accepts glucose. Named, Glycogenin accepts glucose from UDP-glucose. The enzyme that transfers the first glucose from UDP-glucose to Glycogenin is the glycogen initiator synthase. Then glycogenin itself does the same (takes glucose residues itself). And forms a fragment of primer that takes the remaining glucose.

3) Synthesis of Glycogen by Glycogen Synthase:

     The enzyme that is responsible for alpha-1,4-glycosidic linkage formation is glycogen synthase. It transfers the glucose residue from UDP-glucose to the non-reducing end of glycogen and forms alpha-1,4-linkages.

4) Branching of Glycogen: 

     After the synthesis of the linear glycogen chain by the enzyme glycogen synthase, the branching of glycogen starts. The enzyme that catalyzes this reaction is the Branching enzyme named glucosyl-alpha-4,6-transferase, which transfers fragments of 5-8 glucose residue from a non-reducing end to another glucose, forming alpha-1,6-glycosidic linkages. Further elongation and branching occur with the help of respective enzymes. In the end, glycogen is formed.

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Glycogenolysis

     The dissolution of stored glycogen in the liver and muscles into glucose with the help of different enzymes is called Glycogenolysis. The site for glycogenolysis is Cytosol in the liver and muscles, but the difference is that the end product of glycogenolysis in the liver is Glucose, but in the muscles, it is Glucose-6-phosphate because there is the absence of glucose-6-phosphatase.     The dissolution of glycogen occurs by the breakage of alpha-1,4-glycosidic linkages and alpha-1,6-glycosidic linkages. Following are the different steps of glycogenolysis:

1) Glycogen Phosphorylase Enzyme Action:

     Glycogen phosphorylase is the key enzyme in this process, as its main function is to remove glucose successively from the glycogen molecule. The alpha-1,4-glycosidic linkages are cleaved by glucose phosphorylase yielding glucose-1-phosphate,  by a process called Phosphorolysis. This step continues until a limit dextrin is formed (limit dextrin is a remaining fragment of glycogen molecule whose joining point has 4 glucose residues on each side).

2) Action of Debranching Enzyme:

     The branches of glycogen are cleaved by two different activities, done by a single enzyme named Debranching enzyme, that's why it is also called Bifunctional enzyme. 
     The first activity is of Transferase, in which glucose at branches are cleaved, and bonded to the linear chain (glucose are cleaved from alpha-1,4-linkages, and bonded by alpha-1,4-linkages again, but in different positions).     
     The next activity is Glucosidase, in which the single glucose at alpha-1,6-linkage is cleaved and released as free glucose. Then the remaining glycogen is available for phosphorylase and debranching enzymes.

3) Glucose-6-phosphate and Glucose formation:

     The formation of glucose-1-phosphate and free glucose occurs in the ratio of 8:1, after the action of Glycogen phosphorylase and Debranching enzyme. Then, by the action of the Phosphoglucomutase enzyme, conversion of glucose-1-phosphate occurs. Which leads to the conversion of Glucose-1-phosphate to glucose-6-phosphate. The fate of glucose-6-phosphate depends on the tissues, in which it is present. If Glucose-6-phosphate is present in the tissues of the liver, intestine, and kidney, then it will convert into free glucose.  But if G6P is present in tissues of the brain and muscles, the production of free glucose can not take place. That's why the Liver is termed as the main glycogen storage organ of the body due to its supply of free glucose to the blood for its maintenance.

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Regulation of Glycogen Metabolism

     To maintain the blood glucose level, there should be regulation of glycogen metabolism. The enzymes that regulate it are glycogen synthase and glycogen phosphorylase. These enzymes regulate completely with these three mechanisms, that are:

• Allosteric regulation
• Hormonal regulation 
• Effect of Ca ions on glycogenolysis

1) Allosteric Regulation of Glycogen Metabolism:

     There are few metabolites that allosterically regulate glycogen metabolism. The substrate availability and increase energy levels cause the synthesis of glycogen. While when there is less concentration of glucose and energy, the glycogen breakdown starts.      
     The high availability of glucose-6-phosphate initiates the production of glycogen by allosterically activating Glycogen synthase. On the other hand, glucose-6-phosphate and ATP allosterically inhibit Glycogen phosphorylase, also free glucose in the liver causes their inhibition.

2) Hormonal Regulation of Glycogen Metabolism:

Hormones like Insulin and Glucagon regulate glycogen metabolism, called Hormonal Regulation. These hormones do the modifications like phosphorylation and dephosphorylation of enzymes that ultimately control the glycogen synthesis and inhibition.

i) cAMP as a Second Messenger for Hormones: The hormones like epinephrine and glucagon (in the liver) activate the Adenylate cyclase, which increases the production of cAMP. Phosphodiesterase cleaves the cAMP, and Insulin enhances the activity of phosphodiesterase, which lowers the level of cAMP.

ii) Regulation of Glycogen Synthesis by cAMP: Glycogen synthase regulates the synthesis of glycogen in the dephosphorylated state. Phosphorylation of glycogen synthase causes inhibition of glycogen synthesis occurs. This Phosphorylation occurs through cAMP-dependent protein kinase. cAMP-dependent protein kinase catalyzes the phosphorylation of glycogen synthase. But, an enzyme Protein phosphatase-I causes dephosphorylation of glycogen synthase.

iii) Regulation of Glycogen Degradation by cAMP: The hormones like Glucagon and Epinephrine bring glycogenolysis by activating Glycogen phosphorylase with the help of cAMP. The activation of protein kinase then leads to the activation of Glycogen Phosphorylase kinase by its phosphorylation. The active phosphorylase kinase phosphorylates the inactive glycogen phosphorylase to active glycogen phosphorylase that degrades glycogen.

3) Effects of Ca ions on Glycogenolysis: 

     Muscle contraction causes Ca ions to release from the sarcoplasmic reticulum. Then Calcium ions bind with Calmodulin-Calcium modulating protein, which then directly activates the glycogen phosphorylase without acting on cAMP.

Conclusion of Glycogen Metabolism Regulation

     Overall, the increase in the level of Glucagon or Epinephrine leads to the activation of Glycogen phosphorylase, causing Glycogenolysis. But the increase in the level of Insulin will result in increased glycogen synthesis.

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