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Class 4 gluconeogenesis
- 1. Glucose form non carbohydrate source Gluconeogenesis
- 2. Gluconeogenesis • Synthesis of new glucose • Also called as endogenous glucose production • Required because – • Testes, Erythrocyte and renal medulla exclusively use glucose for ATP. • Brain requires glucose but in starvation can adapt to use ketone bodies • To clear lactic acid from skeletal muscle and erythrocyte
- 3. Gluconeogenesis • Failure of gluconeogenesis leads to Hypoglycemia causes brain dysfunction , leads to coma and may be death. • Ketoacidosis, Lactic acidosis • Excessive gluconeogenesis leads to hyperglycemia
- 4. Gluconeogenesis • Major site of Gluconeogenesis • Liver – contribute 85%, • Kidney -- kidney and intestine contributes 15% • During prolonged fasting kidney contribute up to 40% • Gluconeogenic substances • Pyruvate, Lactate, Glycerol, Propionic acid • Glycogenic amino acids --Alanine, glutamine,
- 5. Gluconeogenesis • Pathways involved in gluconeogenesis are • TCA cycle • glycolysis --- Reversal of seven reactions • Some special reactions like • Cori cycle and Glucose alanine cycle • Adipose tissue -- Glycerol • Consumes six moles of ATP per glucose synthesized
- 6. Key reactions of gluconeogenesis Involves Conversion of 1. pyruvate to phosphoenolpyruvate 2. Fructose 1,6 Bisphosphate to Fructose 6 Phosphate 3. Glucose 6 Phosphate to Glucose
- 7. Key Enzymes of gluconeogenesis Pyruvate Phosphoenol Pyruvate 1. Pyruvate carboxylase 2. PEP carboxy kinase Fructose 1,6 Bisphosphate Fructose 6 Phosphate 3. Fructose 1,6 Bis Phosphatase Glucose Glucose 6 Phosphate 4. Glucose 6 Phosphatase
- 8. Gluconeogenesis from Lactate Pyruvate Lactate NADH + H + NAD+ Lactate DH Lactate produced in skeletal muscle , RBC brought to liver by cori cycle In cytosol Pyruvate Enters mitochondria
- 9. Cytoplasm Mitochondria Oxaloacetate Pyruvate Pyruvate Lactate NADH + H + NAD+LDH Malate ADP + Pi CO2 + ATP Pyruvate carboxylase (Biotin) NADH + H + NAD+ MDH 1 Malate Oxaloacetate PEP XNADPH + H + NADP+ MDH 2 PEP CK First bypass reaction in gluconeogenesis Malate shunt GTP GDP + CO2
- 10. 1 2 3 4 5 Pyruvate to Phosphoenol pyruvate
- 11. Reversal of glycolysis Phosphoenol pyruvate 2- Phosphoglycerate 3- Phosphoglycerate 1,3- Bis Phosphoglycerate Glyceraldehyde 3- phosphate Fructose 1-6 Bisphosphate Reactions of glycolysis Takes place in cytosol
- 12. Bypass 2 Fructose-1,6-bisphosphate to Fructose-6- phosphate Enzyme is present in Liver, kidney and skeletal muscle Absent in heart and smooth muscle Fructose 1, 6 BisPhosphate Fructose 6 Phosphate Fructose 1,6 BisPhosphatease H2O Pi Inhibitores -- AMP, F2,6 BP , Insulin Activators -- ATP, Citrate, Glucagon X
- 13. Bypass 3 Glucose-6-phosphate to Glucose • Glucose 6 Phosphatase is found only in liver and kidney • Absent in muscle & adipose tissue , brain • (Reaction takes place in smooth endoplasmic reticulum) Glucose 6 Phosphate Glucose Glucose 6 Phosphatase H2O Pi Glucagon Insulin X
- 15. Regulation of Gluconeogenesis The metabolic control of gluconeogenesis is done by controlling the key enzymes of irreversible steps Activators / inducers Inhibitors / repressors Glucagon Acetyl CoA Citrate, ATP Glycogenic amino acids Fasting state / Carbohydrate feeding Insulin AMP hyperglycemia Diabetes
- 16. Significance of Gluconeogenesis • Keep blood glucose level stable • Remove lactate form skeletal muscle, RBC • Supply glucose to active skeletal muscle • Replenish liver Glycogen • Utilizes glycerol and propionate from adipose tissue • Regulate acid base balance
- 17. Energetics of Gluconeogenesis • Two high energy phosphate bonds one from ATP and one from GTP are hydrolyzed during conversion of pyruvate to PEP • As 2 Pyruvate required for one glucose 2 ATP and 2 GTP are used • Two more ATP required for conversion of 3-PG to 1,3-BPG • Therefore total Six ATP required for one glucose synthesis • In addition NADH is used up and hence 6 ATP lose
- 19. Triacyl glycerol glycerol Free fatty Acid glycerol glycerol Glycerol 3 phosphate DHAP Glyceraldehyde 3 P Glucose Glucose For Extrahepatic TissueGlycerokinase G3PDH
- 21. Cori cycle removal of Lactate and replenishing of glucose to skeletal muscle Pathway in contracting and relaxing skeletal muscle Gluconeogenesis in liver from lactate
- 23. Why skeletal muscle require Cori cycle? In active skeletal muscle mitochondria is less NADH / NAD ratio is low as compared to liver and heart mus Hence to continue glycolysis and generate ATP Reduction of pyruvate is required this generates Lactate If Lactate accumulate it causes Lactic acidosis Hence it should be removed through cori cycle.
- 24. Glucose alanine cycle Important in starvation Gluconeogenesis form Glycogenic amino acids
- 26. Lactate Pyruvate Pyruvate Alanine Oxaloacetate Malate Malate Oxaloacetate PEP 3 P Glycerate 2 P Glycerate 1,3 BPG G 3 P F 1,6,BPF 6 PG 6 PGlucose DHAP 3 P G Glycerol Aspartate Succinyl CoA Propionate α-KG Citrate
- 27. Gluconeogenesis