Pathway
Gluconeogenesis is a pathway consisting of a series of eleven enzyme-catalyzed reactions. The pathway may begin in the mitochondria or cytoplasm, this being dependent on the substrate being used. Many of the reactions are the reversible steps found in glycolysis.
- Gluconeogenesis begins in the mitochondria with the formation of oxaloacetate by the carboxylation of pyruvate. This reaction also requires one molecule of ATP, and is catalyzed by pyruvate carboxylase. This enzyme is stimulated by high levels of acetyl-CoA (produced in β-oxidation in the liver) and inhibited by high levels of ADP.
- Oxaloacetate is reduced to malate using NADH, a step required for its transportation out of the mitochondria.
- Malate is oxidized to oxaloacetate using NAD+ in the cytosol, where the remaining steps of gluconeogenesis take place.
- Oxaloacetate is decarboxylated and then phosphorylated to form phosphoenolpyruvate using the enzyme phosphoenolpyruvate carboxykinase. A molecule of GTP is hydrolyzed to GDP during this reaction.
- The next steps in the reaction are the same as reversed glycolysis. However, fructose-1,6-bisphosphatase converts fructose-1,6-bisphosphate to fructose 6-phosphate, using one water molecule and releasing one phosphate. This is also the rate-limiting step of gluconeogenesis.
- Glucose-6-phosphate is formed from fructose 6-phosphate by phosphoglucoisomerase. Glucose-6-phosphate can be used in other metabolic pathways or dephosphorylated to free glucose. Whereas free glucose can easily diffuse in and out of the cell, the phosphorylated form (glucose-6-phosphate) is locked in the cell, a mechanism by which intracellular glucose levels are controlled by cells.
- The final reaction of gluconeogenesis, the formation of glucose, occurs in the lumen of the endoplasmic reticulum, where glucose-6-phosphate is hydrolyzed by glucose-6-phosphatase to produce glucose. Glucose is shuttled into the cytoplasm by glucose transporters located in the endoplasmic reticulum's membrane.
| Metabolism of common monosaccharides, including glycolysis, gluconeogenesis, glycogenesis and glycogenolysis |
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—Friedrich Nietzsche (1844–1900)
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“Socrates drinking the hemlock,
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—William Herbet Carruth (1859–1929)