Gluconeogenesis

Gluconeogenesis refers to the synthesis of glucose, which takes place in the cytosol via a similar pathway to glycolysis. While at glance it may seem that the reactions are the same but reversed, there are 3 irreversible reactions in glycolysis that must be bypassed in gluconeogenisis.

These irreversible reactions are:

  • conversion of phosphophenolpyruvate to pyruvate using pyruvate kinase (step 10)

  • phosphorlyation of fructose-6-phosphate to fructose-1,6-bisphosphate by phosphofructokinase-1 (step 3)

  • conversion of glucose to glucose-6-phosphate by hexokinase (step 1)


1st irreversible reaction

To overcome the first challenge, two different enzymes are used together in gluconeogenesis

  • Pyruvate carboxylase converts pyruvate into oxaloacetate inside the mitochondria

    • activated by acetyl-CoA derived from B-oxidation of fatty acids

  • Oxaloacetate is reduced to malate to exit the mitochondria, but converts back to oxaloacetate once in the cytoplasm

  • Phosphoenolpyruvate carboxykinase (PEPCK) converts oxaloacetate into phosphoenolpyruvate

    • requires GTP as a phosphoryl donor, creating GDP


As the pathway moves forward, the second challenge arises with the irreversible reaction of the phosphorylation of fructose-6-phosphate. This is overcome by the use of fructose-1,6-bisphosphatase

  • Whereas enzymes ending in -kinase add phosphate groups, enzymes ending in -phosphatase remove phosphate groups

  • Fructose-1,6-bisphosphatese removes the 1’ phosphate group via hydrolysis

  • This is the rate-limiting step of gluconeogenesis


final irreversible reaction

The final bypass involves the 1st step of glycolysis, which is the initial phosphorylation of glucose to glucose-6-phosphate. Gluconeogenesis utilizes a second phosphatase to overcome this step,

  • Glucose-6-phosphatase, which is located in the ER, removes the phosphate group on glucose-6-phosphate to convert it back to glucose

  • Glucose is then transported back into the cytoplasm, and enters circulation