Gluconeogenesis .Gluconeogenesis reaction
- 1. Dr Sikandar Ali Khan MBBS, MPhil, DCP, CHPE
- 2. The synthesis of glucose from non- carbohydrate compounds is known as gluconeogenesis.
- 3. The major substrates/precursors for gluconeogenesis: Lactate Pyruvate glucogenic amino acids Propionate glycerol.
- 4. Site: Gluconeogenesis occursmainly in the liver, and to a lesser extent in the renal cortex.
- 5. Site: The pathway ispartly mitochondrial & partly cytoplasmic. About 1kg glucose synthesized everyday
- 6. Brain &CNS, erythrocytes, testes &kidney medulla are dependent on glucose for continuous supply for energy.
- 7. Human brain alone requires about 120g of glucose per day, out of about 160g needed by the entire body. Glucose is the only source that supplies to the skeletal muscle, anaerobic conditions.
- 8. During starvation gluconeogenesis maintains the blood glucose level. The stored glycogen is depleted within the first 12-18hours of fasting.
- 9. On prolonged starvation, the gluconeogenesis is speeded up &protein catabolism provides the substrates, namely glucogenic amino acids.
- 10. Gluconeogeenesis closely resembles the reversed pathway of glycolysis.
- 11. The 3irreversible steps of glycolysis are catalysed by the 3enzymes. Hexokinase PFK Pyruvate kinase
- 12. These three stages bypassed by alternate enzymes specific to gluconeogenesis. These are: Pyruvate carboxylase Phosphoenol pyruvate carboxy kinase Fructose-1-6-bisphosphatase Glucose-6-phosphatase
- 14. Takes place in two steps pyruvate carboxylase is a biotin dependent mitochondrial enzyme that converts pyruvate to oxaloacetate in presence of ATP & CO2
- 15. This enzyme regulates gluconeogenesis & requires acetyl CoAfor its activity.
- 16. Oxaloacetate is synthesized in the mitochondrial matrix. It has to be transported to the cytosol.
- 18. Due to membrane impermeability, oxaloacetate cannot diffuse out of the mitochondria. It is converted to malate &transported to cytosol. In the cytosol, oxaloacetate is regenerated.
- 19. The reversible conversion of oxaloacetate to malate is catalysed by MDH, present in mitochondria & cytosol In the cytosol, phosphoenolpyruvate carboxykinase converts oxaloacetate to phosphoenol pyruvate.
- 20. GTPor ITP (not ATP) is used in this reaction and the CO2is liberated. For the conversion of pyruvate to phosphoenol pyruvate, 2ATP equivalents are utilized.
- 21. Phosphoenolpyruvate undergoes the reversal of glycolysis until Fructose 1,6-bisphosphate is produced.
- 23. The enzyme Fructose 1,6-bisphosphatase converts Fructose 1,6-bisphosphate to Fructose 6-phosphate &it requires Mg2+ ions. Thisis also a regulatory enzyme.
- 24. Glucose 6-phosphatase catalyses the conversion of glucose 6-phosphate to glucose.
- 25. It is present in liver &kidney but absent in muscle, brain and adipose tissue. Liver can replenish blood sugar through gluconeogenesis, glucose 6-phosphatase is present mainly in liver.
- 30. The carbon skeleton of glucogenic amino acids (all except leucine &lysine) results in the formation of pyruvate or the intermediates of citric acid cycle. Which, ultimately, result in the synthesis of glucose.
- 33. Glycerol is liberated in the adipose tissue by the hydrolysis of fats (triacylglycerols). The enzyme glycerokinase (found in liver & kidney, absent in adipose tissue) activates glycerol to glycerol 3- phosphate.
- 34. It is converted to DHAP by glycerol 3- phosphate dehydrogenase. DHAP is an intermediate in glycolysis.
- 37. Oxidation of odd chain fatty acids &the breakdown of some amino acids (methionine, isoleucine) yields a three carbon propionyl CoA.
- 38. Propionyl CoA carboxylase acts on this in the presence of ATP & biotin & converts to methyl melonyl CoA
- 39. Which isthen converted to succinylCoA in the presence of B12. Succinyl CoA formed from propionyl CoA enters gluconeogenesis.
- 40. GLUCOGENESIS FROM Lactate (Cori Cycle)
- 41. Definition: It is a process in which glucose is converted to Lactate in the muscle and in the liver this lactate is re-converted to glucose.
- 42. In an actively contracting muscle, pyruvate is reduced to lactic acid which may tend to accumulate in the muscle. Toprevent lactate accumulation, body utilizes cori cycle.
- 43. Thislactic acid from muscle diffuses into the blood. Lactate then reaches liver, where it is oxidised to pyruvate.
- 44. It is entered into gluconeogenesis. Regenerated glucose can enter into blood and then to muscle. Thiscycle is called cori cycle.
- 45. Cori Cycle
- 46. Cori Cycle
- 47. Gluconeogenesis &glycolysis are reciprocally regulated One pathway is relatively inactive when the other is active.
- 48. Regulatory enzymes: Pyruvate Carboxylase. Fructose-1,6-bisphosphatase. ATP . Hormonal Regulation of Gluconeogenesis.
- 49. It is an allosteric enzyme. Acetyl CoA is an activator of pyruvate carboxylase so that generation of oxaloacetate is favored when acetyl CoA level is high.
- 50. Citrate is an activator. Fructose-2,6-bisphosphate & are inhibitors. All these three effectors have an exactly opposite effect on the phosphofructokinase (PFK). ATP: Gluconeogenesis is enhanced by ATP .
- 51. Glucagon & glucocorticoids increase gluconeogenesis Glucocorticoids induce the synthesis of hepatic amino transferases & provides substrate for gluconeogenesis.
- 52. The high glucagon-insulin ratio favors induction of synthesis of gluconeogenic enzymes (PEPCK,Fructose-1,6-bisphosphatase & glucose-6-phosphatase). At the same time, synthesis of glycolytic enzymes HK, PFK&PK are depressed.