2. Gluconeogenesis

Last updated on January 11, 2020 at 14:17


  • Produces glucose from pyruvate, lactate, glycerol and certain amino acids
    • But NOT from acetyl-CoA or fatty acids
    • Glycerol comes from the glycerol part of triacylglycerols
  • Takes place mainly in the liver, but also the renal cortex and intestinal epithelial cells.
  • Uses 7 of the enzymes used in glycolysis (but in reverse), but uses 4 exclusive enzymes
    • The exclusive ones are
      • Pyruvate carboxylase
      • PEP carboxykinase
      • Fructose 1,6-bisphosphatase-1
      • Glucose 6-phosphatase
  • Occurs mainly in cytosol, except Pyruvate Carboxylase which is in the mitochondria and G6Pase which is in ER
    • PEP carboxykinase exists in both cytosol and mitochondria


Comparison of glycolysis and gluconeogenesis. Note the enzymes that are different, and that 2 pyruvate are needed for the formation of 1 glucose.

Pyruvate is transported from the cytosol into the mitochondria, where the pyruvate carboxylase converts pyruvate to oxaloacetate. However, oxaloacetate cannot be transported into the cytosol, as there is no transporter for it. OAA is therefore reduced to malate by mitochondrial malate dehydrogenase, passed into the cytosol as malate, and converted back into OAA in the cytosol by cytosolic malate dehydrogenase. Here, OAA is converted into phosphoenolpyruvate by PEP carboxykinase, which uses one GTP.

From PEP, gluconeogenesis follows the same path as glycolysis until it reaches fructose 1,6-bisphosphate. Here, fructose 1,6-bisphosphatase converts F16BP to fructose 6-phosphate. Following the conversion of F6P to glucose 6-phosphate, glucose 6-phosphatase (found in ER) converts G6P to glucose.

Lactate can be converted into pyruvate by lactate dehydrogenase. This pyruvate then follows the pathway outlined above.

Because there exists no enzyme in humans that can convert acetyl-CoA to pyruvate, fatty acids cannot be broken down to acetyl-CoA to yield glucose.


Running glycolysis and gluconeogenesis at the same time would be a complete waste of energy. As both processes happen in the cytosol, they are reciprocally (oppositely) regulated, so that when one runs, the other stops. Regulation is covered in a later chapter.

Cori cycle and alanine cycle

As RBC’s don’t have mitochondria, they can only produce energy anaerobically (without oxidative phosphorylation) from glucose via the glycolysis, which yields lactate. The same process happens in muscle during periods of hard work, when oxygen supply is limited. The lactate produces in these cases are transported to the liver, where it is converted to glucose. This glucose is excreted into the bloodstream, which travels back to the muscle as part of a cycle called the Cori cycle.

Another similar cycle is the alanine cycle. This doesn’t take place in RBC’s as it depends on an enzyme (ALT) that is only present in muscle and the liver. The enzyme converts pyruvate and glutamate into alanine and α-ketoglutarate. Alanine is transported in the blood to the liver, where the alanine is converted back to pyruvate and glutamate. The former is converted to glucose, the latter loses its amino group, which goes into the urea cycle. The alanine cycle is therefore used to recycle pyruvate from muscle, and also remove ammonia from it.

Fates of pyruvate

Pyruvate has many possible fates in the liver:

  • Conversion to oxaloacetate and then PEP to be used in gluconeogenesis
  • Conversion to acetaldehyde
    • By pyruvate decarboxylase
  • Conversion to alanine
    • By alanine transaminase
  • Conversion to lactate
    • By lactate dehydrogenase
  • Conversion to acetyl-CoA to be used as a substrate for the TCA cycle
  • etc.

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1. Pentose phosphate pathway

Next page:
3. Glycogen synthesis and degradation

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