Gluconeogensis its regulation by Benish Akhtar
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Gluconeogensis its regulation by Benish Akhtar
- 2. Presented to:- Sir Shehroz Khan Presented to:- Benish Nasir Khan Topic Gluconeogensis its regulation and significance
- 3. Gluoconeogenesis • Is the formation of glucose from non- carbohydrate sources e.g lactic acid ,amino acids , glycerols and propionate. • Site: liver and kidney.
- 4. Gluoconeogenesis • Occurs in all animals, plants, fungi and microbes • Occurs largely in the liver; some in renal cortex • Of 10 enzymatic steps, 7 are reversals of glycolytic reactions
- 5. Gluoconeogenesis • Gluconeogenesis begins with various substrates converted into pyruvate.and this proceed though what is essentially the reverse of glycosis(except for a few committed steps). • 3 and 4-carbon substrates can enter the gluconeogenesis pathway. Lactate from anaerobic exercise in skeletal muscle is easily converted to pyruvate; this happens as part of the Cori cycle.
- 6. Gluoconeogenesis • Oxaloacetate (an intermediate in the citric acid cycle can also be used for gluconeogenesis. Amino acids, after their amino group has been removed, feed into parts of the citric acid cycle, and can thus can generate glucose in this pathway. • Fatty acids cannot be turned into glucose, as they are broken down into the two carbon acetyl CoA. (However glycerol which is a part of all triacylglycerides can be used in gluconeogenesis).
- 7. PHYSIOLOGICAL SIGNIFICANCE OF GLUCONEOGENESIS • Gluconeogenesis is particularly important in liver control of blood glucose homeostasis. • Gluconeogenesis allows synthesis of glucose for times when liver glycogen reserves are substantially depleted; during fasting (before breakfast) and during starvation.
- 8. PHYSIOLOGICAL SIGNIFICANCE OF GLUCONEOGENESIS • Unlike most tissues, glucose can easily diffuse out of hepatocytes into the blood. • Because hepatocytes contain much more of the glycolysis enzyme glucokinase (KM ~ 10mM) than hexokinase (KM = 0.1mM) most glucose synthesised in the liver is unlikely to be converted to glucose 6-phosphate.
- 9. glucose glucose 6- phosphate fructose 6- phosphate fructose 1,6- bisphosphate phosphoenolpyruvate pyruvate hexokinase Phosphofructokinase-1 pyruvate kinase fructose bisphosphatase glucose 6-phosphatase GLUCONEOGENESIS GLYCOLYSIS oxaloacetate pyruvate carboxylase phosphoenolpyruvate carboxykinase
- 10. • (1) Pyruvate to phosphoenolpyruvate • Pyruvate is first converted to oxaloacetate by the enzyme pyruvate carboxylase. • Oxaloacetate is then converted to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase. GLUCONEOGENESIS: ‘By-Pass’ Reactions COOH | C = O | CH3 pyruvic acid COOH | C = O | CH2 | COOH oxaloacetic acid COOH | C – O – PO || CH2 phosphoenolpyruvic acid CO2 ATP ADP + Pi GTP GDP CO2
- 11. GLUCONEOGENESIS: ‘By-Pass’ Reactions (2) Fructose 1,6-bisphosphate to Fructose 6- phosphate Catalysed by fructose bisphosphatase. OH O CH2O – PO CH2O – PO 3 2 OH HOH H H α-D-fructose 1,6-bisphosphate 3 2 OH O CH2O – PO CH2OH 3 2 OH HOH H H α-D-fructose 6-phosphate H2O Pi
- 12. GLUCONEOGENESIS: ‘By-Pass’ Reactions (3) Glucose 6-phosphate to glucose Catalysed by glucose 6-phosphatase. H2O Pi O CH2OH HO OH OH OH α-D-glucose HH H H H O CH2O – PO HO OH OH OH HH H α-D-glucose 6-phosphate 3 2 H H Glucose 6-phosphatase is chiefly found in liver cells where it is important for producing glucose to ‘top-up’ blood glucose levels. It is absent in muscle cells.
- 13. GLUCONEOGENESIS from lactate/pyruvate The Cori Cycle Glucose pyruvate lactate Glucose pyruvate lactate blood blood Muscle/ Erythrocytes Liver glycolysis gluconeogenesis
- 14. Glycerol, from the breakdown of triglycerides can also provide a raw material for gluconeogenesis. glycerol glycerol 3- phosphate dihydroxyacetone phosphate glucose gluconeogenesis GLUCONEOGENESIS FROM TRIGLYCERIDES Acetyl CoA, the main breakdown product of fatty acids, cannot be used to feed gluconeogenesis.
- 15. Fructose 2,6-bisphosphate is the most important regulator of glycolysis and gluconeogenesis. REGULATION OF GLYCOLYSIS/GLUCONEOGENESIS Fructose 2,6-bisphosphate is not an intermediate of either pathway but is synthesised from fructose 6-phosphate by a dual function enzyme known as phosphofructokinase- 2/fructose 2,6-bisphosphatase. Fructose 2,6-bisphosphate stimulates phosphofructokinase activity (glycolysis) inhibits fructose bisphosphatase activity (gluconeogenesis)
- 16. glucose glucose 6- phosphate fructose 6- phosphate fructose 1,6- bisphosphate phosphoenolpyruvate pyruvate hexokinase PFK-1 pyruvate kinase fructose bisphosphatase glucose 6- phosphatase stimulation inhibition fructose 2,6- bisphosphate PFK-2 GLUCONEOGENESIS GLYCOLYSIS
- 17. REGULATION OF GLYCOLYSIS/GLUCONEOGENESIS Reversible phosphorylation of phosphofructokinase-2 / fructose 2,6-bisphosphatase controls the activity of this enzyme. fructose 6- phosphate fructose 2,6-bisphosphate concentration decreases phosphofructokinase -2 activity inhibited fructose 2,6-bisphosphatase activity stimulated by phosphorylation Enables gluconeogenesis Effects of phosphorylation: Inhibits glycolysis
- 18. REGULATION OF GLYCOLYSIS/GLUCONEOGENESIS Reversible phosphorylation of phosphofructokinase-2 / fructose 2,6-bisphosphatase controls the activity of this enzyme. fructose 6- phosphate fructose 2,6-bisphosphate concentration increases phosphofructokinase-2 activity stimulated by dephosphorylation fructose 2,6-bisphosphatase activity inhibited Inhibits gluconeogenesis Stimulates glycolysis Effects of dephosphorylation:
- 19. Regulation of Glycolysis/Gluconeogenesis Synthesis and degradation of the regulator fructose 2,6- bisphosphate is controlled by reversible phosphorylation of the enzyme phosphofructokinase-2 / fructose 2,6- bisphosphatase by protein kinase A. Phosphorylation turns on phosphofructokinase-2 / fructose 2,6-bisphosphatase activity Dephosphorylation turns on: phosphofructokinase-2 / fructose 2,6-bisphosphatase activity
- 20. glucose glucose 6- phosphate fructose 6- phosphate fructose 1,6- bisphosphate phosphoenolpyruvate pyruvate hexokinase Phosphofructokinase-1 pyruvate kinase fructose bisphosphatase glucose 6-phosphatase AMP, Pi ATP, citrate AMP stimulation inhibition AMP GLUCONEOGENESIS GLYCOLYSIS
- 21. Regulation of Glycolysis/Gluconeogenesis The pancreatic hormone glucagon stimulates gluconeogenesis glucagon protein kinase A PFK-2/fructose 2,6- bisphosphatase – OH fructose 6- bisphosphate fructose 2,6- bisphosphate PFK-2/fructose 2,6- bisphosphatase – P Removal of fructose 2,6-bisphosphate stimulates gluconeogenesis and inhibits glycolysis G-protein / cAMP signalling cascade
- 22. Regulation of Glycolysis/Gluconeogenesis The pancreatic hormone insulin inhibits gluconeogenesis insulin protein kinase A PFK-2/fructose 2,6- bisphosphatase – OH fructose 6- bisphosphate fructose 2,6- bisphosphate PFK-2/fructose 2,6- bisphosphatase – P Presence of fructose 2,6-bisphosphate inhibits gluconeogenesis and stimulates glycolysis
- 23. Thank you