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Glycogen metabolism part-2

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An overview of glycogen degradation

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Glycogen metabolism part-2

  1. 1. Glycogen metabolism- Part-2 (Glycogen degradation) Namrata Chhabra, M.D., Biochemistry 1/6/2017Namrata Chhabra, M.D., Biochemistry 1
  2. 2. Learning objectives  To understand:  The Purpose  Role of Enzymes and coenzymes, and  The steps involved in the pathway of Glycogenolysis 1/6/2017Namrata Chhabra, M.D., Biochemistry 2
  3. 3. Introduction  Glycogen is a storage form of glucose.  It is a very large, branched polymer of glucose residues that can be broken down to yield glucose molecules when energy is needed.  Most of the glucose residues in glycogen are linked by α-1,4- glycosidic bonds.  Branches at about every tenth residue are created by α-1,6- glycosidic bonds. 1/6/2017Namrata Chhabra, M.D., Biochemistry 3
  4. 4. Glycogen structure 1/6/2017Namrata Chhabra, M.D., Biochemistry 4
  5. 5. Purpose of Glycogenolysis  The controlled breakdown of glycogen and release of glucose increase the amount of glucose that is available between meals. Hence, glycogen serves as a buffer to maintain blood-glucose levels.  Glycogen's role in maintaining blood glucose levels is especially important because glucose is virtually the only fuel used by the brain, except during prolonged starvation. 1/6/2017Namrata Chhabra, M.D., Biochemistry 5
  6. 6. Purpose of Glycogenolysis  The glucose from glycogen is readily mobilized and is therefore a good source of energy for sudden, strenuous activity.  Unlike fatty acids, the released glucose can provide energy in the absence of oxygen and can thus supply energy for anaerobic activity. 1/6/2017Namrata Chhabra, M.D., Biochemistry 6
  7. 7. Enzymes involved in Glycogenolysis  The efficient breakdown of glycogen requires four enzyme activities:  one to degrade glycogen,  two to remodel glycogen so that it remains a substrate for degradation, and  one to convert the product of glycogen breakdown into a form suitable for further metabolism. 1/6/2017Namrata Chhabra, M.D., Biochemistry 7
  8. 8. Enzymes of Glycogenolysis Phosphorylase Bifunctional- Debranching enzyme Phospho- glucomutase Glucose-6- Phosphatase 1/6/2017Namrata Chhabra, M.D., Biochemistry 8
  9. 9. Major coenzyme of Glycogenolysis  Pyridoxal phosphate (PLP), a derivative of vitamin B6, is the major coenzyme involved in the glycogen degradation.  serves as prosthetic group for Glycogen Phosphorylase.  It is held at the active site of Phosphorylase enzyme by a Schiff base linkage, formed by reaction of the aldehyde group of PLP with the ε-amino group of a lysine residue. 1/6/2017Namrata Chhabra, M.D., Biochemistry 9
  10. 10. Glycogen degradation is not just the reverse of glycogenesis Glycogenesis  Glucose-> Glucose-6-P  Glucose-6-P –> Glucose-1-P  Polymerization  Branching  Polymerization  Glycogenolysis  Depolymerization- Removal of glucose as glucose-1-P  Debranching  Depolymerization  Conversion of Glucose-1-P to Glucose-6-P  Conversion of Glucose-6-P to free Glucose 1/6/2017Namrata Chhabra, M.D., Biochemistry 10
  11. 11. Specific steps of Glycogenolysis  Step-1- Depolymerization (Release of Glucose-1-P from Glycogen)  Enzyme- Phosphorylase  Coenzyme– Pyridoxal phosphate  Reaction involved : 1/6/2017Namrata Chhabra, M.D., Biochemistry 11
  12. 12. Step-1- Reaction catalyzed by Phosphorylase  Phosphorylase catalyzes the sequential removal of glucosyl residues from the nonreducing ends of the glycogen molecule (the ends with a free 4-OH group.  Orthophosphate splits the glycosidic linkage between C-1 of the terminal residue and C-4 of the adjacent one. 1/6/2017Namrata Chhabra, M.D., Biochemistry 12
  13. 13. Phosphoroyltic cleavage Why not hydrolytic cleavage ? 1/6/2017Namrata Chhabra, M.D., Biochemistry 13
  14. 14. Advantages of Phosphoroyltic cleavage  The phosphoroylytic cleavage of glycogen is energetically advantageous because the released sugar is already phosphorylated.  In contrast, a hydrolytic cleavage would yield glucose, which would then have to be phosphorylated at the expense of the hydrolysis of a molecule of ATP to enter the glycolytic pathway.  An additional advantage of phosphoroylytic cleavage for muscle cells is that glucose 1-phosphate, negatively charged under physiological conditions, cannot diffuse out of the cell. 1/6/2017Namrata Chhabra, M.D., Biochemistry 14
  15. 15. Problem with Phosphorylase  The α-1,6-glycosidic bonds at the branch points are not susceptible to cleavage by phosphorylase.  Glycogen phosphorylase stops cleaving α -1,4 linkages when it reaches a terminal residue four residues away from a branch point.  Because about 1 in 10 residues is branched, glycogen degradation by the phosphorylase alone would come to a halt after the release of six glucose molecules per branch. 1/6/2017Namrata Chhabra, M.D., Biochemistry 15
  16. 16. Step-2- Remodeling and Debranching  Special Bifunctional enzyme with two enzyme activities  Transferase and Debranching (α-1,6- glucosidase)  Both these enzymes remodel the glycogen for continued degradation by the phosphorylase. 1/6/2017Namrata Chhabra, M.D., Biochemistry 16
  17. 17. Role of Transferase  Transferase shifts a block of three glucosyl residues from one outer branch to the other.  This transfer exposes a single glucose residue joined by an α-1,6-glycosidic linkage.  Debranching enzyme, hydrolyzes the α -1, 6- glycosidic bond, resulting in the release of a free glucose molecule.  The transferase and α-1,6-glucosidase convert the branched structure into a linear one, which paves the way for further cleavage by phosphorylase. 1/6/2017Namrata Chhabra, M.D., Biochemistry 17
  18. 18. Phosphorylase versus debranching enzyme- Outcomes  Glucose-1-P is released as an outcome of reaction catalyzed by Phosphorylase  Free glucose is released by the action of debranching enzyme 1/6/2017Namrata Chhabra, M.D., Biochemistry 18
  19. 19. Step-3- Conversion of Glucose-1-P to Glucose-6-P  Phosphoglucomutase converts glucose 1-phosphate into glucose 6- phosphate in a reversible reaction.  The catalytic site of an active mutase molecule contains a phosphorylated serine residue.  The phosphoryl group is transferred from the serine residue to the C-6 hydroxyl group of glucose 1-phosphate to form glucose 1,6- bisphosphate.  The C-1 phosphoryl group of this intermediate is then shuttled to the same serine residue, resulting in the formation of glucose 6- phosphate and the regeneration of the phosphoenzyme. 1/6/2017Namrata Chhabra, M.D., Biochemistry 19
  20. 20. Reaction catalyzed by Phosphoglucomutase 1/6/2017Namrata Chhabra, M.D., Biochemistry 20
  21. 21. Step-4- Fate of Glucose-6-P  Glucose 6-phosphate derived from glycogen can  (1) be used as a fuel for anaerobic or aerobic metabolism as in, for instance, muscle;  (2) be converted into free glucose in the liver and subsequently released into the blood;  (3) be processed by the pentose phosphate pathway to generate NADPH or ribose in a variety of tissues. 1/6/2017Namrata Chhabra, M.D., Biochemistry 21
  22. 22. The fate is different in liver and muscle  The liver contains a hydrolytic enzyme, glucose 6-phosphatase, which cleaves the phosphoryl group to form free glucose and orthophosphate.  Glucose 6-phosphatase is absent from most other tissues. Consequently, glucose 6-phosphate is retained for the generation of ATP.  In contrast, glucose is not a major fuel for the liver. The liver releases glucose into the blood during muscular activity and between meals to be taken up primarily by the brain and skeletal muscle. 1/6/2017Namrata Chhabra, M.D., Biochemistry 22
  23. 23. Reaction catalyzed by Glucose-6- Phosphatase 1/6/2017Namrata Chhabra, M.D., Biochemistry 23
  24. 24. Glycogenesis versus Glycogenolysis • Glycogenolysis and Glycogenesis are not the just the reverse of each other. • The reaction pathways, enzymes and coenzymes are all different and, • both the ways are reciprocally regulated. 1/6/2017Namrata Chhabra, M.D., Biochemistry 24
  25. 25. Regulation of glycogen metabolism  To be continued in the next section… 1/6/2017Namrata Chhabra, M.D., Biochemistry 25
  26. 26. Thank you 1/6/2017Namrata Chhabra, M.D., Biochemistry 26

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