Gluconeogenesis and glycogenolysis


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Gluconeogenesis and glycogenolysis

  3. 3. Gluconeogenesis is a metabolic pathway occurring in living beings for synthesis of glucose from non-carbohydrate precursors. It converts pyruvate and its related three- and four-carbon compounds into glucose. It is an irreversible process . It occurs in cytosol.
  4. 4. PATHWAY  CONVERSION OF PYRUVATETO PHOSPHOENOL PYRUVATE (PEP)- Pyruvate is transported from cytosol to mitochondria or generated from alanine by transamination within mitochondria.Then, pyruvate carboxylase, an enzyme that uses biotin as a co- enzyme; converts pyruvate to oxaloacetate. PYRUVATE + HCO₃⁻ + ATP  OXALOACETATE + ADP + Pi Because mitochondrial membrane has no transporter for oxaloacetate, so pyruvate is reduced to malate by malate dehydrogenase at the expense of NADH. OXALOACETATE + NADH + H⁺ ↔ L-MALATE + NAD⁺
  5. 5. Malate leaves the mitochondrion through a specific transporter in the inner mitochondrial membrane and in cytosol, it is re-oxidised to oxaloacetate, with the production of cytosolic NADH. MALATE + NAD⁺OXALOACETATE + NADH + H⁺ The oxaloacetate is then converted to PEP by phosphoenolpyruvate carboxykinase. OXALOACETATE + GTP ↔PEP + CO₂ + GDP
  6. 6.  CONVERSION OF PEPTO 2-PHOSPHOGLYCERATE- This step is reverse of the step in glycolysis. This reaction is performed by Enolase.  CONVERSION OF 2-PHOSPHOGLYCERATETO 3- PHOSPHOGLYCERATE- This step is also reverse of the step in glycolysis. This step is catalyzed by the enzyme Phosphoglycerate Mutase.  CONVERSION OF 3-PHOSPHOGLYCERATE TO 1,3- BISPHOSPHOGLYCERATE- This step is reverse of the step in glycolysis as well. This step is catalyzed by Phosphoglycerate Kinase.
  7. 7.  REDUCTION OF 1,3 BISPHOSPHOGLYCERATETO GLYCERALDEHYDE-3-PHOSPHATE – This step is reverse of the step in glycolysis. In this step, 1,3-Bisphosphoglycerate is reduced to Glyceraldehyde-3-phosphate by the enzyme Glyceraldehyde 3-phosphate dehydrogenase.  INTERCONVERSION OFTRIOSE PHOSPHATES- This step is reverse of the step in glycolysis. The Glyceraldehyde 3-phosphate is interconverted to Dihydroxyacetone phosphate byTriose isomerase phosphate.  CONVERSION OF DIHYDROXYACETONE PHOSPHATE TO FRUCTOSE 1,6-BISPHOSPHATE- This step is also reverse of the step in glycolysis. This step is performed by the enzyme Fructose 1,6 BisphosphateAldolase.
  8. 8.  CONVERSION OF FRUCTOSE 1,6 BISPHOSPHATETO FRUCTOSE 6- PHOSPHATE – This is an irreversible step where Fructose 1,6 Bisphosphate is converted to Fructose 6- Phosphate by the Mg⁺⁺-dependent enzyme, Fructose 1,6 Bisphosphatase which promotes the hydrolysis of the C-1 phosphate. Fructose 1,6 Bisphosphate + H₂O  Fructose 6- Phosphate + Pi
  9. 9.  CONVERSION OF FRUCTOSE 6-PHOSPHATE TO GLUCOSE 6-PHOSPHATE – This step is reverse of the step in glycolysis.This reversible conversion of a ketose to an aldose is done by the enzyme Phosphohexose Isomerase.  CONVERSION OF GLUCOSE 6- PHOSPHATE TO GLUCOSE- It is the final reaction of gluconeogenesis where Glucose 6-Phosphate is dephosphorylated to yield Glucose by another Mg⁺⁺-dependent enzyme Glucose 6-Phosphatase. Glucose 6-Phosphate + H₂O  Glucose + Pi
  10. 10. THE THREE BYPASS REACTIONS Almost all the steps of Gluconeogenesis are reverse of Glycolysis except three reactions- 1. CONVERSION OF PYRUVATETO PHOSPHOENOL PYRUVATE 2. CONVERSION OF FRUCTOSE 1,6 BISPHOSPHATETO FRUCTOSE 6- PHOSPHATE 3. CONVERSION OF GLUCOSE 6- PHOSPHATETO GLUCOSE Here a different set of enzymes are utilized than Glycolysis and are characterized by a large –ve free energy change, ∆G whereas in the other reactions, the value of ∆G is near to 0.
  11. 11. REGULATION There are 3 steps involved in regulation of Gluconeogenesis. 1. CONVERSION OF PYRUVATE TO OXALOACETATE- When the cell’s energy need is being met, oxidative phosphorylation slows down, NADH:NAD⁺ rises and inhibits citric acid cycle due to which Acetyl-CoA accumulates. Since Acetyl-CoA is an positive allosteric modulator of Pyruvate Carboxylase, it stimulates gluconeogenesis and increases the formation of glucose from pyruvate.
  12. 12. 2. CONVERSION OF FRUCTOSE 1,6- BISPHOSPHATETO FRUCTOSE 6- PHOSPHATE- The enzyme FBPase-1 involved in this reaction is strongly inhibited by AMP. So, when a high proportion of the cell’s adenylate is in the form of ATP, gluconeogenesis is favored.
  13. 13. 3. HORMONAL REGULATION OF GLUCONEOGENESIS- The hormonal regulation of gluconeogenesis is mediated by Fructose 2,6-Bisphosphate, an allosteric effector for the enzyme FBPase-1.The hormones epinephrine and glucagon decreases the concentration of Fructose 2,6-Bisphosphate by raising cAMP and bringing about phosphorylation, i.e., inactivation of PFK-2 and activates FBPase-2 leading to breakdown of Fructose 2,6-Bisphosphate. Insulin increases the concentration of Fructose 2,6-Bisphosphate by dephosphorylating PFK-2.
  15. 15. Glycogenolysis is a metabolic process by which glycogen, the primary carbohydrate stored in the liver and muscle cells of animals, is broken down into glucose to provide immediate energy and to maintain blood glucose levels during fasting. Glycogen is catabolized by removal of a glucose monomer through cleavage with inorganic phosphate to produce glucose-1- phosphate.This derivative of glucose is then converted to glucose-6-phosphate, an intermediate in glycolysis. It takes place in the muscle and liver tissues, where glycogen is stored, as a hormonal response to epinephrine and/or glucagon.
  16. 16. PATHWAY  First step- The overall reaction for the 1st step is: Glycogen (n residues) + Pi ↔ Glycogen (n-1 residues)+ G1P Here, glycogen phosphorylase cleaves the bond at the C1 position by substitution of a phosphoryl group. It breaks down glucose polymer at [α14] linkages until 4 linked glucoses are left on the branch. Pyridoxal phosphate is an important co- factor in this reaction, as its phosphate group acts as a general acid catalyst, promoting attack by Pi on the glycosidic bond.
  17. 17.  Second step- The second step involves the enzyme oligo α[1→6] to α[1→4] glucantransferase or debranching enzyme, which transfers the three remaining glucose units to another 1,4 terminal of glycogen, which exposes the α[1→6] branching point. The final action of this enzyme is the hydrolysis of the remaining glucose attached at the α[1→6] branch point, which gives one free glucose molecule.
  18. 18.  Third step- The third and last stage converts G1P (glucose-1-phosphate) to G6P (glucose-6- phosphate) through the enzyme phosphoglucomutase. G1P ↔ G6P Here the enzyme donates a phosphoryl group to C-6 of the substrate and accepts a phosphoryl group from C-1.
  19. 19. FATES OF GLUCOSE 6 PHOSPHATE  This G6P can enter glycolysis and serve as an energy source to support muscle contraction.  In liver, it releases glucose into blood when blood glucose level drops.
  20. 20. REGULATION OF GLYCOGEN PHOSPHORYLASE  Glycogen phosphorylase is activated in response to Glucagon or Epinephrine which raise the [cAMP] level and activate Protein KinaseA. PKA phosphorylates and activates Phosphorylase Kinase, which converts Glycogen Phosphorylase B to its active A form.  Phosphoprotein Phosphatase 1 reverses the phosphorylation of Glycogen Phosphorylase A, inactivating it.  Glucose binds to the liver isozyme of Glycogen Phosphorylase,favoring its dephosphorylation and inactivation.
  21. 21. REFERENCES  Lehninger’s principles of Biochemistry by David L. Nelson and Michael M. Cox   Britannica Online Encyclopaedia