Class 4 gluconeogenesis
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Dr. Dhiraj J. Trivedi presenting Lecture on Carbohydrate metabolism for medical students. Professor, SDM College of Medical Sciences, Dharwad, Karnataka, India
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Class 4 gluconeogenesis
- 2. Gluconeogenesis • Synthesis of new glucose • Also called as endogenous glucose production • Required because – • Erythrocyte, lens, testes 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 • To some extent reduce NH3 toxicity
- 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. 85% 15% Gluconeogenesis • Major site of Gluconeogenesis • Liver – contribute 85%, • Kidney -- kidney and intestine contributes 15% • But - During prolonged fasting kidney can 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 Lactate produced in skeletal muscle , RBC brought to liver by Cori cycle Pyruvate Lactate NADH + H + NAD+ Lactate DH 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 X NADPH + 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. Reversible steps of glycolysis Phosphoenol pyruvate 2- Phosphoglycerate 3- Phosphoglycerate 1,3- Bis Phosphoglycerate Glyceraldehyde 3- phosphate Fructose 1-6 Bisphosphate Reactions taking 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 Free Glucose Glucose 6 Phosphatase H2O Pi Glucagon Insulin X
- 15. Regulation of Gluconeogenesis controlled by Regulating key enzymes of irreversible steps Activators / inducers Inhibitors / repressors Glucagon Acetyl CoA Citrate, ATP Glycogenic amino acids Carbohydrate feeding Insulin AMP Fasting state / hypoglycemia 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 • Also NADH is used up and hence additional 6 ATP lose
- 19. Triacyl glycerol glycerol Free fatty Acid glycerol glycerol Glycerol 3 phosphate DHAP Glyceraldehyde 3 P Glucose Glucose For Extra hepatic Tissue Glycerokinase G3PDH
- 21. Cori cycle removal of Lactate and replenishing of glucose to skeletal muscle Pathway operate in active 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 muscle 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. Glucose Pyruvate Lactate Alanine Amino acid Glutamate Keto glutarate Glucose Pyruvate Alanine Urea Keto glutarate Glutamate
- 27. CitrateMalate Fumarate Succinyl CoA α -Ketoglutarate Oxaloacetate oxalosuccinate Aspartate Glutamic acid Histidine Proline Hydroxyproline Arginine Ornithine Valine Isoleucine Methionine Phenylalanine Tyrosine Glycine Serine Alanine Cysteine Threonine Pyruvate Entry of amino acids in TCA cycle
- 28. Thank you