Regulation of Gluconeogenesis

Figure 16.6 shows the primary control mechanisms of glycolysis and gluconeogenesis. These include allosteric controls of the primary enzymes, hormonal control of enzyme synthesis, and general hormonal regulation. Gluconeogenesis and glycolysis both proceed primarily in the cytosol. Because gluconeogenesis synthesizes glucose and glycolysis catabolizes glucose, the two opposing pathways are controlled in reciprocal fashion. Otherwise, a futile cycle would result.

The control points for the pathways are also the places where the two pathways employ different enzymes. Notice that some compounds, such as fructose-2,6-bisphosphate (F2,6BP), AMP, and acetyl-CoA have opposite effects on activities of enzymes in the two pathways. This is one of the mechanisms of the reciprocal regulation.

The enzymes of gluconeogenesis and the mechanisms by which they are controlled are summarized as follows:

> Glucose-6-phosphatase - This enzyme is not known to be allosterically controlled. Its K M for G6P is far higher than intracellular concentrations of the metabolite. Intracellular activity is controlled in first-order fashion by the concentration of G6P.

> Fructose 1,6 bisphosphatase - The primary regulatory enzyme for gluconeogenesis. Inactivated potently by F2,6BP (See Figure 16.17) and AMP. Synthesis of the enzyme is sensitive to hormonal control.

> Phosphoenolpyruvate carboxykinase (PEPCK) - This enzyme has no known allosteric regulators. The enzyme is controlled by hormonal regulation of its synthesis. The hormone, glucagon, activates transcription of the structural gene for the enzyme. Insulin, on the other hand, inhibits transcription of the gene.

> Pyruvate carboxylase - This enzyme is found only in the mitochondrial matrix, apart from the other enzymes of glycolysis and gluconeogenesis. It can be activated by acetyl-CoA, but it is not clear what role it has in the overall control of the enzyme, since cellular levels of acetyl-CoA are far higher, under most conditions, than the concentration giving half-maximal stimulation.

See also: Gluconeogenesis/Glycolysis Links Page, Reciprocal Regulation, Relationship of Gluconeogenesis to Glycolysis, Role of Fructose-2,6-Bisphosphate in Gluconeogenesis Regulation