gluconeogenesis

• Gluconeogenesis


  The metabolic pathway through which glucose is synthesized from non-carbohydrate precursors
• Conversion of Pyruvate to Oxaloacetate


  1. Enzyme: Pyruvate carboxylase

  2. Reaction: Pyruvate+HCO3−+ATP→Oxaloacetate (OA)+ADP+Pi

  3. Location: Mitochondria

  4. Regulation: Allosterically activated by acetyl-CoA

  5. Mechanism: Formation of carboxyl phosphate, Transfer to biotin forming carboxybiotinyl-enzyme, Transfer of carboxyl group to pyruvate to form oxaloacetate

  6. Importance: Provides a critical link between carbohydrate and lipid metabolism
• Transport of Oxaloacetate to Cytoplasm

  1. Mechanism: Oxaloacetate is converted to malate or aspartate, transported across the mitochondrial membrane, and then reconverted to oxaloacetate in the cytoplasm

  2. Importance: Ensures the generation of NADH in the cytoplasm without directly producing NADH inside the mitochondrion
• Conversion of Oxaloacetate to Phosphoenolpyruvate (PEP)

  1. Enzyme: PEP carboxykinase

  2. Reaction: Oxaloacetate+GTP→PEP+GDP+CO2

  3. Location: Cytoplasm

  4. Regulation: Transcriptionally regulated by hormones such as glucagon and cortisol

  5. Mechanism: Decarboxylation and phosphorylation of oxaloacetate to form PEP, bypassing the irreversible step of glycolysis catalyzed by pyruvate kinase
• Conversion of Fructose-1,6-bisphosphate to Fructose-6-phosphate


  1. Enzyme: Fructose-1,6-bisphosphatase (FBPase-1)

  2. Reaction: Fructose-1,6-bisphosphate+H2O→Fructose-6-phosphate+Pi

  3. ΔG: -16.3 kJ/mol (irreversible hydrolysis)

  4. Regulation: Key regulatory point in gluconeogenesis, inhibited by AMP and fructose-2,6-bisphosphate, and activated by citrate

  5. Importance: Bypasses the phosphofructokinase-1 (PFK-1) step of glycolysis, which is highly regulated
• Conversion of Glucose-6-phosphate to Glucose

  1. Enzyme: Glucose-6-phosphatase

  2. Reaction: Glucose-6-phosphate+H2O→Glucose+Pi

  3. ΔG: -13.8 kJ/mol

  4. Location: Endoplasmic reticulum of liver cells (and kidneys), ensuring release of free glucose into the bloodstream

  5. Regulation: Glucose-6-phosphatase activity is controlled by substrate availability and hormonal regulation (insulin inhibits, glucagon and epinephrine stimulate)

  6. Importance: Critical for maintaining blood glucose levels, especially during fasting
• Cori Cycle


  Recycles lactate produced by anaerobic glycolysis in muscles back into glucose in the liver
• Cori Cycle


  1. In Muscle: Glucose is converted to pyruvate, then to lactate under anaerobic conditions

  2. Transport: Lactate is transported via the bloodstream to the liver

  3. In Liver: Lactate is converted back to pyruvate, then to glucose via gluconeogenesis
• Lactate Dehydrogenase


  Converts pyruvate to lactate, regenerating NAD⁺ (in muscle)

  Converts lactate back to pyruvate, utilizing NAD⁺ (in liver)
• Precursors for Gluconeogenesis


  • Lactate
  • Glycerol
  • Glucogenic Amino Acids: Alanine, Cysteine, Glycine, Serine, Threonine, Tryptophan (to Pyruvate), Arginine, Glutamate, Glutamine, Histidine, Proline (to α-Ketoglutarate), Isoleucine, Methionine, Threonine, Valine (to Succinyl-CoA), Aspartate, Asparagine (to Oxaloacetate)
• Overall Reaction of Gluconeogenesis

  2Pyruvate+4ATP+2GTP+2NADH+6H2O→Glucose+4ADP+2GDP+6Pi+2NAD++2H+

  ΔG: -38 kJ/mol, indicating the process is energetically favorable but costly in terms of ATP and GTP
• Gluconeogenesis


  • It is not the exact reverse of glycolysis; it bypasses the irreversible steps of glycolysis with distinct enzymes
  • Essential for maintaining blood glucose levels during fasting or intense exercise
  • Involves the conversion of non-carbohydrate precursors into glucose, which is critical for tissues that rely on glucose as a primary energy source
  • Energetically expensive but essential for survival during periods of low carbohydrate intake