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  1. 1. Gluconeogenesis Dr. Waheeda Nargis Associate Professor Dept. of Biochemistry, UAMCH
  2. 2. Gluconeogenesis The process of synthesis of glucose or glycogen from non-carbohydrate sources is called Gluconeogenesis. Substrates for Gluconeogenesis: Glucogenic amino acid Glycerol Pyruvate Lactate Intermediates of TCA cycle MCQ: Followings are the substrates for gluconeogenesis- a) Alanine, b) Leucine, c) Glycerol d) Acetyl CoA e) Fatty Acid
  3. 3. Features of Gluconeogenesis Site: Liver (90%) , Kidney(10%),Intestinal epithelial cells (negligible) On overnight fasting  90% site is Liver & the rest in Kidney. On prolonged fasting  60% site is Kidney & the rest in liver Compartment: Cytoplasm (mitochondria also participates) Nature: Anabolic; 6 ATP needed for synthesis of one glucose from 2 pyruvate or lactate. Pathways involved in gluconeogenesis  Reverse glycolysis,  TCA cycle,  Some special reactions like:  Cori cycle,  Glucose alanine cycle.
  4. 4. Key Steps & Enzymes of Gluconeogenesis Fructose-1,6- bisphosphate Fructose-6- phosphate Glucose Glucose-6- phosphate Pyruvate Oxaloacetate PEPOxaloacetate pyruvate carboxylase PEP carboxykinase fructose-1,6-bisphosphatase glucose-6-phosphatase
  5. 5. Pathways involved for Alanine, Aspartate, Glutamate. Gluconeogenesis from Amino Acids
  6. 6. Gluconeogenesis from glycerol Glycerol Glycerol kinase Glycerol-3 phosphate DHA-P glycerol-3-phosphate dehydrogenase The initial phosphorylation of glycerol takes place at liver rather than adipocytes since they lack the enzyme glycerol kinase. (The shortest pathway) Glyceraldehyde -3 phosphateReverse glycolysis DHA-P : Dihydroxyacetone phosphate
  7. 7. Cori Cycle The pathway of gluconeogenesis from lactate. Substrate: Lactate Site: liver, Background: Absence of Glucose - 6 phosphatase in skeletal muscle .
  8. 8. Glucose Glucose 2 Pyruvate 2 Pyruvate 2 Lactate 2 Lactate MUSCLE LIVERBLOOD 2 ATP 6 ATP Anaerobic Glycolysis Gluconeogenesis Fig: The Cori Cycle
  9. 9. Lactate from tissue sources of anaerobic glycolysis (e.g-skeletal muscle) is transferred to the liver In liver, Lactate is converted to pyruvate to finally produce glucose Return of newly synthesized glucose to the sources for reutilization. Steps
  10. 10. Glucose- Alanine Cycle
  11. 11. Biomedical Importance of Gluconeogenesis • To maintain the blood glucose concentration during prolonged fasting or starvation when sufficient carbohydrate is not available from the diet or glycogen reserves. • It maintains the level of intermediates of the TCA cycle even when fatty acids are the main source of acetyl coA in the tissues. • It clears the lactate produced by muscle and erythrocytes and glycerol produced by adipose tissue.
  12. 12. Malate Shuttle • Malate transporter in mito. Membrane • malate dehydrogenase in both mito and cytoplasm Interlinking of mitochondrial & Cytosolic Pathways • OAA produced in mitochondria is impermeable across the Mitochondrial membrane Thus , OAA must be converted into malate or asparate, exported from the mitochondrion, and converted back into oxaloacetate in order to allow gluconeogenesis to continue.
  13. 13. Pyruvate is transported from the cytoplasm to the mitochondria. In the mitochondria, pyruvate is converted to oxaloacetate by pyruvate carboxylase Oxaloacetate can not be transported to the cytoplasm. Oxaloacetate is reduced in the mitochondria to malate: Malate dehydrogenase Oxaloacetate + NADH + H+ Malate + NAD+ Malate is transported to the cytoplasm and reoxidized back to oxaloacetate: Malate dehydrogenase Malate + NAD+ Oxaloacetate + NADH + H+
  14. 14. Regulation of Gluconeogenesis The metabolic control of gluconeogenesis is done by controlling the key steps and enzymes. Main Regulatory Hormones are: Glucagon, Insulin. Effects: Glucagon stimulates gluconeogenesis.