Biochemistry. Glycogenolysis. Metabolism of Carbohydrates. Dr.S.K.Khare,Professor IIT Delhi. Principal Investigator

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1 Paper : 04 Metabolism of carbohydrates Module : 24 Dr. Vijaya Khader Dr. MC Varadaraj Principal Investigator Paper Coordinator Content Reviewer Dr.S.K.Khare,Professor IIT Delhi. Dr. Ramesh Kothari,Professor UGC-CAS Department of Biosciences Saurashtra University, Rajkot-5, Gujarat-INDIA Dr. S. P. SinghProfessor UGC-CAS Department of Biosciences Saurashtra University, Rajkot-5, Gujarat-INDIA Content Writer Dr.VikramRaval,Assistant Professor UGC-CAS Department of Biosciences Saurashtra University, Rajkot-5, Gujarat-INDIA 1

2 Description of Module Subject Name Paper Name Module Name/Title 04 Metabolism of carbohydrates 24 2

3 GLYCOGENOLYSIS Objectives 1. To understand the breakdown of glycogen. 2. To understand the role of glycogen phosphorylase in glycogen breakdown. 3. To understand the role of Glycogen Debranching enzyme 3

4 Introduction The biological degradation of glycogen is termed as 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 bond at about every tenth residues. Fig: 25.1 STRUCTURE OF GLYCOGEN Glycogen founds in the cytoplasm as granules. Granules also contain the enzymes and regulatory proteins which is required for its synthesis and degradation.it acts as an important energy reserve for the body. 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. Regulation of glycogenesis and glycogenolysis is very important in maintaining the glycogen homeostasis. These two processes are commonly regulated. Hormones which stimulate glycogenolysis (e.g. glucagon, cortisol, epinephrine, nor 4

5 epinephrine) concurrently inhibit glycogenesis. On the other hand, insulin, which promotes the body to store glycogenesis, is inhibiting glycogenolysis. Glycogen is degraded by two different pathways. In the first, glucose is released in muscles to fuel its contraction or it is released in liver to transport it in to the blood. It is catalysed by the Glycogen phosphorylase and Debranching enzyme. In the second pathway, glycogen is degraded to glucose within the lysosome by the enzyme α-glucosidase and acid maltase. Glycogen metabolism is very important because it facilitate the blood glucose level to be maintained between meals (liver glycogen) and also act as an energy reserve for muscular activity. The maintenanceof blood glucose is essential in order to supply energy to tissues. GLYCOGEN GLUCOSE Fig: 24.1 leads to formation of glucose STEPS OF GLYCOGENOLYSIS requires2main enzymes. occurs by a different pathwayfrom glycogenesis. 5

6 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-phosphateby Phosphoglucomutase. Glycogen phosphorylase GLYCOGEN (n residues) GLUCOSE-1-PHOSPHATE Pi GLYCOGEN (n-1 residues) Phosphoglucomutase GLUCOSE-6-PHOSPHATE Glucose-6-Phosphatase (In liver) GLUCOSE Diffuse in to the bloodstream Fig: 24.2OVERVIEW OF GLYCOGENOLYSIS 1. Glucose-1-phosphate formation from non reducing end of glycogen by Glycogen phosphorylase Glycogen is broken-down in to Glucose-1-Phosphate (G1P) by Glycogen Phosphorylase. It is carried out by phosphorolysis reaction. Phosphorolysis 6

7 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 bond. GLYCOGEN (n residues) HPO4-2 GLYCOGEN PHOSPHORYLASE GLYCOGEN (n -1) Cleavage by phosphorolysis Fig: 24.3 Formation is energetically of G-1-P favourable from glycogen because released glucose is phosphorylated. While hydrolytically release of sugar needs to be phosphorylated before enters into the glycolytic pathway. 7

8 Glycogen phosphorylase act on exoglycosidic bond. Pyridoxal phosphate is an 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. Glycogen phosphorylase is an allosteric enzyme. AMP acts as an allosteric activator while ATP, G6P and glucose acts as an allosteric inhibitor. Glycogen phosphorylase is also regulated by covalent modification. ( For further details please refer module:26, regulation of glycogen degradation) Generally in the structure of glycogen about 1 in 10 residues is branched. In such situation phosphorylase enzyme 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 while 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 enzyme shows two differentactivities. o Transferase activity o α 1 6 glucosidase activity In transferase activity, the enzyme removes and transfers terminal 3 of the 4 glucose residues. It transfers this moiety intact to the non reducing end of another 8

9 branch. It involves cleaving of an α (1 4) linkage and formation of new α (1 4) linkage in another branch. This action leaves a single glucose at the α1,6 branch. In α 1 6 glucosidase activity, enzyme removes the single glucose residue which is remaining at branch point by an alpha (1 6 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 enzyme. Remaining about 8 % are converted to glucose by the α 1 6 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. Active site of the active Phosphoglucomutase molecule has a phosphorylated serine residue. The phosphoryl group istransferred from the amino acid serine to the hydroxyl group (C-6) of glucose 1-phosphate. It result in to the formation of intermediate called glucose1, 6-bisphosphate. The phosphoryl group from the C-1 9

10 of glucose 1, 6-bisphosphate is then transfer to the serine residue of the enzyme. It results in to the formation of glucose 6-phosphate and the regeneration of the enzyme. This reaction is reversible. It allows the inter conversion of Glucose-6-Phosphate and Glucose-1-Phosphate. This isvery important. Phosphoglucomutase is also required to form. Phosphoglucomutase GLUCOSE-1-PHOSPHATE (Phosphoryl group from serine residue transferred to G-1-P) GLUCOSE-1-6-BISPHOSPHATE Phosphoglucomutase (Phosphoryl group from G-1-6-P transferred to serine residue of enzyme) GLUCOSE-6-PHOSPHATE Fig: 24.4 Formation of G-6-P from G-1-P 10