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Glycogen metabolism & gluconeogenesis -Carbohydrate metabolic pathways for glucose homeostasis

Glycogen metabolism & gluconeogenesis -Carbohydrate metabolic pathways for glucose homeostasis. GLYCOGEN METABOLISM. Liver glycogen. Muscle glycogen. maintains blood glucose. supplies energy during muscle contraction. Introduction. Storage form of carbohydrates in animals. Glycogen:.

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Glycogen metabolism & gluconeogenesis -Carbohydrate metabolic pathways for glucose homeostasis

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  1. Glycogen metabolism & gluconeogenesis-Carbohydrate metabolic pathways for glucose homeostasis

  2. GLYCOGEN METABOLISM

  3. Liver glycogen Muscle glycogen maintains blood glucose. supplies energy during muscle contraction.

  4. Introduction Storage form of carbohydrates in animals Glycogen: Sites: Liver & muscle Functions Liver glycogen is used to maintain blood glucose. Muscle glycogen supplies energy during muscle contraction.

  5. Glycogenesis It is the synthesis of glycogen from glucose. Tissue : Liver & muscle Intracellular site : Cytosol Glycogen primer Requirements : UTP, ATP Reactions : • Synthesis of UDP-Glucose. • Synthesis of primer to initiate glycogen • Elongation of glycogen chains by glycogen synthase • Formation of branches in glycogen.

  6. 1. Synthesis of UDP-Glucose. Glucose ATP glucokinase (liver) ADP hexokinase (muscle) Glucose-6- phosphate phosphoglucomutase Glucose-1- phosphate UTP UDP-glucose pyrophosphorylase PPi UDP -glucose ( UDP - )

  7. 2. Synthesis of primer to initiate glycogen UDP glycogenin OH UDP Glycogen primer

  8. 3. Elongation of glycogen chains by glycogen synthase Glycogen primer 13 UDP Glycogen synthase 13 UDP

  9. 4.Formation of branches in glycogen. Branching enzyme 1-6- bond

  10. 4.Formation of branches in glycogen. 1-6- bond Elongation by glycogen synthase Formation of branches by branching enzyme Glycogen

  11. Glucose ADP glucokinase (liver) ATP hexokinase (muscle) Glucose-6- phosphate phosphoglucomutase Glucose-1- phosphate UDP-glucose pyrophosphorylase PPi UTP (UDP - UDP -glucose glycogenin OH Glycogen initiator synthase UDP Glycogen primer 13 UDP Glycogen synthase 13 UDP Branching enzyme Elongation by glycogen synthase Formation of branches by branching enzyme Glycogen

  12. Glycogenolysis It is the degradation of glycogen stored in liver and muscle to glucose. Glycogenolysis is not the reverse of the glycogenesis but is a separate pathway . Liver & muscle Tissue : Cytosol Intracellular site : Reactions : • Action of glycogen phosphorylase. • Action of debranching enzyme. • Formation of glucose -6 - phosphate.

  13. Action of glycogen phosphorylase. Glycogen Pi Glycogen phosphorylase Limit dextrin

  14. Action of debranching enzyme. Limit dextrin Debranching enzyme (transferase activity) Debranching enzyme (1,6 glucosidase) glucose

  15. Formation of glucose -6 - phosphate. Further action of glycogen phosphorylase Glucose-1- phosphate phosphoglucomutase muscle Glucose-6- phosphate glycolysis Glucose -6-phosphatase (liver ,kidney ) Glucose

  16. Glycogen Glycogen phosphorylase Limit dextrin Debranching enzyme (transferase activity) Debranching enzyme (1,6 glucosidase) Further action of glycogen phosphorylase Glucose-1- phosphate Glucose-6- phosphate Glucose

  17. Regulation of glycogen metabolism

  18. Regulation of glycogen metabolism Glycogenesis and glycogenolysis are controlled by the enzymes glycogen synthase and glycogen phosphorylase. Regulation of these enzymes is accomplished by 2 mechanisms 1.Covalent modification -brought about by Hormones 2.Allosteric regulation. -brought about by substrates

  19. Regulation of glycogen metabolism... glycogen synthase and glycogen phosphorylaseare said to be RECIPROCALLY REGULATED That is, when one enzyme is active, the other one is inactive. RECIPROCALLY REGULATION is brought about by hormones, by COVALENT MODIFICATION OF THE 2 ENZYMES.

  20. COVALENT MODIFICATION OF THE 2 ENZYMES -Addition or removal of a group (phosphate group) makes the enzyme either active or inactive. glycogen phosphorylase is active in PHOSPHORYLATED Form. (inactive in dephoshorylated form) glycogen synthase is active in DEPHOSPHORYLATED Form. (inactive in phoshorylated form)

  21. Hormonal regulation -mainly by 3 hormones; 1. epinephrine 2.glucagon 3. insulin-In fed state

  22. Allosteric regulation. Glucose 6-po4, and ATP are allosteric modulators. They activate Glycogen synthase Inhibit glycogen phoshorylase

  23. Glycogen storage disorders The enzymes defect may be either generalized (affecting all tissues) or tissue-specific (liver, muscle, kidney, intestine, myocardium) They result in either formation of glycogen that has an abnormal structure or the accumulation of excessive amounts of normal glycogen in specific tissues.

  24. Glycogen storage disorders

  25. II

  26. Gluconeogenesis

  27. Gluconeogenesis Definition The synthesis of glucose from non – carbohydrate substrates. Substrates • lactate • Glycerol • Glucogenic amino acids • Propionate Sites: Liver (90%) kidney (10%) Sub cellular sites: Partly mitochondrial & partly cytosolic

  28. Significance of gluconeogenesis 1.Maintenance of blood glucose,when glycogen stores are depleted. -Tissues such as brain , RBC , require a continous supply of glucose as a source of energy . Liver glycogen meets these needs for 12-18 hrs .As the glycogen stores starts depleting, gluconeogenesis ensures continous supply of glucose to tissues . 2. removes the products of metabolism eg; lactate produced in the muscle , propionate and glycerol.

  29. Characteristics Glycolysis and gluconeogenesis share the same pathway but in opposite direction. Gluconeogenesis utilizes all the seven enzymes of glycolysis catalyzing reversible reactions Gluconeogenesis also utilizes four special enzymes (the so called key enzymes of gluconeogenesis) for catalyzing the reversal of the three irreversible reactions of glycolysis

  30. Glucose- 6- phosphatase is only present in liver and kidney but not in the muscle. Thus muscle cannot provide blood glucose by gluconeogenesis.

  31. Reactions of gluconeogenesis 1. Carboxylation of pyruvate to oxaloacetate 2. Transport of oxaloacetate to cytosol 3. Decarboxylation of cytosolic oxaloacetate to phospho enol pyruvate (PEP). 4. Dephosphorylation of fructose -1,6-bisphosphate to fructose-6- phosphate 5. Dephosphorylation of glucose -6-phosphate to glucose

  32. 1. Carboxylation of pyruvate to oxaloacetate mitochondria Pyruvate biotin,mg2+ ATP+CO2 Pyruvate carboxylase ADP+Pi oxaloacetate Cytoplasm

  33. 2. Transport of oxaloacetate to cytosol Pyruvate Oxaloacetate oxaloacetate Malate dehydrogenase NADH malate Malate dehydrogenase malate NAD+ Cytoplasm Malate shuttle

  34. 3. Decarboxylation of cytosolic oxaloacetate to phospho enol pyruvate (PEP). Phospho enol pyruvate GDP+CO2 Phospho enol pyruvate carboxy kinase GTP Pyruvate Oxaloacetate oxaloacetate malate malate Cytoplasm

  35. 4. formation of fructose -1,6-bisphosphate by reversal of glycolysis Fructose-1,6-bisphosphate Glyceraldehyde – 3- phosphate Dihydroxy acetone phosphate 1,3-bisphosphoglycerate Cytoplasm 3-phosphoglycerate 2-phosphoglycerate Pyruvate phosphoenolpyruvate oxaloacetate oxaloacetate malate malate

  36. 4. Dephosphorylation of fructose -1,6-bisphosphate to fructose-6- phosphate Fructose -6- phosphate H2 O Fructose- 1,6-bisphosphatase Pi Fructose-1,6-bisphosphate Glyceraldehyde – 3- phosphate Dihydroxy acetone phosphate 1,3-bisphosphoglycerate Cytoplasm 3-phosphoglycerate 2-phosphoglycerate Pyruvate phosphoenolpyruvate oxaloacetate oxaloacetate malate malate

  37. 5. Dephosphorylation of glucose -6-phosphate to glucose Glucose- 6- phosphatase is only present in liver and kidney but not in the muscle. Thus muscle cannot provide blood glucose by gluconeogenesis. glucose glucose- 6-phosphatase glucose-6- phosphate Fructose -6- phosphate Fructose-1,6-bisphosphate Glyceraldehyde – 3- phosphate Dihydroxy acetone phosphate 1,3-bisphosphoglycerate Cytoplasm 3-phosphoglycerate 2-phosphoglycerate Pyruvate phosphoenolpyruvate oxaloacetate oxaloacetate malate malate

  38. Key enzymes of gluconeogenesis glucose 4 glucose- 6-phosphatase glucose-6- phosphate Fructose -6- phosphate Fructose-1,6-bisphosphatase 3 Fructose-1,6-bisphosphate Glyceraldehyde – 3- phosphate Dihydroxy acetone phosphate 1,3-bisphosphoglycerate Cytoplasm 1 3-phosphoglycerate 1 2-phosphoglycerate Pyruvate 2 phosphoenolpyruvate Pyruvate carboxylase Phosphoenolpyruvatecarboxy kinase oxaloacetate oxaloacetate malate malate

  39. Cori’s cycle liver muscle • Cycle that operates between liver and muscle, for efficient utilization of lactate glucose glucose glycolysis gluconeogenesis pyruvate pyruvate NAD+ NADH Lactatedehydrogenase LDH NADH+H+ lactate lactate NADH+H+ blood

  40. Significance Of Coris Cycle Lactate accumulation causes muscle cramps during strenuous muscular exercise Cori’s cycle prevents such excessive accumulation of lactate and ensures efficient reutilization of lactate by the body.

  41. Regulation of gluconeogenesis GLYCOLYSIS AND GLUCONEOGENESIS ARE RECIPROCRALLY REGULATED. Gluconeogenesis is regulated by the following mehanisms: 1.Hormonal regulation (long term regulation) 2.Allosteric regulation (long term regulation)

  42. Regulation of gluconeogenesis… 1.Hormonal regulation (long term regulation) Induction by -Glucagon,epinephrine,glucocorticoids Repression by -insulin 2.Allosteric regulation (long term regulation) -Allosteric inhibition by AMP -Allosteric activation by acetyl CoA

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