Glycogenolysis

Glycogenolysis is the process of breaking down glycogen into glucose. It occurs when blood glucose levels fall, ensuring that normal blood sugar levels are maintained. 

1.0Introduction and Structure of Glycogen

• The biological degradation of glycogen is termed glycogenolysis. Glycogen is a highly branched, large polymer of glucose molecules linked along its main line by α-1, 4 glycosidic linkages; branches arise by α-1,6 glycosidic bonds at about every tenth residue. Glycogen is found in the cytoplasm as granules. 
• Granules also contain the enzymes and regulatory proteins required for their synthesis and degradation. Protein acts as an important energy reserve for the body, and it is stored in the liver and skeletal muscle. 
• Glycogen stored in the muscles will be utilized for the energy requirement of muscles only, while glycogen stored in the liver will be used for the energy requirement of the rest of the body.  
• Regulating glycogenesis and glycogenolysis is very important in maintaining glycogen homeostasis. These two processes are commonly controlled. 
• Hormones which stimulate glycogenolysis (e.g. glucagon, cortisol, epinephrine, norepinephrine) concurrently inhibit glycogenesis. On the other hand, insulin, which promotes the body to store glycogenesis, is inhibiting glycogenolysis. Two different pathways degrade glycogen. 
• In the first pathway, glucose is released in muscles to fuel contraction or in the liver to transport it into the blood. The Glycogen phosphorylase and Debranching enzyme catalyze this. In the second pathway, glycogen is degraded to glucose within the lysosome by the enzymes α-glucosidase and acid maltase.  
• Glycogen metabolism plays a crucial role in maintaining blood glucose levels between meals through liver glycogen. This energy reserve serves as a source of energy for muscle activity. Maintaining blood glucose is essential for providing energy to tissues.

2.0Steps of Glycogenolysis

Glycogenolysis requires two main enzymes. Glycogenolysis occurs by a different pathway from glycogenesis.

1. Glucose-1-phosphate formation from non reducing end of glycogen by Glycogen phosphorylase 

2. Removal of α-1,6 branches from glycogen by Glycogen Debranching enzyme 

3. Glucose-6-phosphate formation from Glucose-1-phosphate by Phosphoglucomutase.

1. Glucose-1-phosphate formation from non reducing end of glycogen by Glycogen phosphorylase:

• Glycogen is broken down into Glucose-1-Phosphate (G1P) by Glycogen Phosphorylase. This is carried out by the phosphorolysis reaction. The phosphorolysis reaction involves the cleavage of larger molecules into smaller molecules. It uses phosphate for the cleavage. Such breakdown of bonds by the addition of orthophosphate is referred to as phosphorolysis. A hydrolysis reaction also involves the same process, but it uses water instead of phosphate for the cleavage of the bond.
• Glycogen phosphorylase acts on exo-glycosidic bonds. Pyridoxal phosphate is a necessary cofactor in the glycogen phosphorylase reaction. 
• This cofactor is linked to lysine 680 of the enzyme. Glycogen phosphorylase will act repeatedly on non-reducing ends of a glycogen chain. 
• Glycogen phosphorylase can act continuously until it reaches 4 glucose away from α 1-6 branch point. It is an allosteric enzyme. AMP acts as an allosteric activator, while ATP, G6P, and glucose act as allosteric inhibitors. 
• Glycogen phosphorylase is also regulated by covalent modification. In such situations phosphorylase enzymes cannot degrade glycogen independently. It will stop to a halt after the release of six glucose molecules per branch. 

2. Removal of α-1,6 branches from glycogen by Glycogen Debranching enzyme :

• In glycogen, α- 1-6 glycosidic bonds at the branch point are not susceptible to cleavage by glycogen phosphorylase. It can act continuously until it reaches four glucose away from α 1-6 branch point. 
• Thus further degradation of glycogen chain by glycogen phosphorylase occurs only after the action of a glycogen debranching enzyme. Glycogen debranching enzymes show two different activities. 

1. Transferase activity 

2. α - 6 glucosidase activity  

• In transferase activity, the enzyme removes and transfers terminal 3 of the 4 glucose residues. It then transfers this moiety intact to the non-reducing end of another branch. 
• It involves cleaving an α (14) linkage and forming a new α (14) linkage in another branch. This action leaves a single glucose at the α1,6 branch. In α 16 glucosidase activity, enzymes remove the single glucose residue, which remains at the branch point, by an alpha (16 glucosidase activity of the same debranching enzyme.  91 % of the glycogen residues are converted to Glucose-1-phosphate by the combined activity of glycogen phosphorylase and glycogen debranching enzymes. 
• The remaining 8 % are converted to glucose by the α 16 glucosidase activity of the glycogen debranching enzyme.

3. Glucose-6-phosphate formation from Glucose-1-phosphate by Phosphoglucomutase:

• Glucose-1-phosphate is converted to Glucose-6-phosphate by Phosphoglucomutase. The active site of the Phosphoglucomutase molecule has a phosphorylated serine residue. 
• The phosphoryl group is transferred from the amino acid serine to the hydroxyl group (C-6) of glucose 1-phosphate, forming an intermediate called glucose 1, 6-bisphosphate. 
• The phosphoryl group from the C-1  of glucose 1, 6-bisphosphate is then transferred to the serine residue of the enzyme. It results in the formation of glucose 6-phosphate and the regeneration of the enzyme. This reaction is reversible. 
• It allows the interconversion of Glucose-6-Phosphate and Glucose-1-Phosphate. This is very important. Phosphoglucomutase is also required to form.