Gluconeogenesis and Glycolysis Regulation Link Page

Gluconeogenesis and glycolysis both proceed largely in the cytosol. Because gluconeogenesis synthesizes glucose and glycolysis catabolizes glucose, it is evident that gluconeogenesis and glycolysis must be controlled in reciprocal fashion. If not for reciprocal control, glycolysis and gluconeogenesis would operate together as a giant futile cycle.

Conditions of low energy charge tend to activate the rate-controlling steps in glycolysis while inhibiting carbon flux through gluconeogenesis. Conversely, gluconeogenesis is stimulated at high energy charge, under conditions where catabolic flux rates are adequate to maintain sufficient ATP levels.

Regulation of the two pathways primarily is brought about by allosteric controls on the enzymes that differ between the two pathways. These enzymes are:

Glyolysis Enzyme | Gluconeogenesis Enzyme

Hexokinase

Glucose-6-phosphatase

Phosphofructokinase-1 (PFK-1) | Fructose 1,6 bisphosphatase

Pyruvate kinase (note on isozymes)

1. Pyruvate Carboxylase

2. Phosphoenolpyruvate carboxykinase (PEPCK)

1. F2,6BP and AMP activate PFK-1 and inhibit Fructose 1,6 bisphosphatase

2. G6P substrate levels control Hexokinase and Glucose-6-phosphatase

3. Acetyl-CoA inhibits Pyruvate kinase and activates Pyruvate Carboxylase

Other control points on the two pathways are shown in Figure 16.6

The major allosteric regulatory factor of the two pathways is Fructose 2,6 bisphosphate. Note in Figure 16.7 that PFK-2 and Fructose 2,6-bisphosphatase are on the same peptide and are affected differently by phosphorylation (see below). Interconversion of PFK-2 and Fructose 2,6-bisphosphatase depends on the level of cAMP (which is stimulated by glucagon and epinephrine and is inhibited by insulin). Increasing cAMP (glucagon/epinephrine) stimulates phosphorylation of PFK-2 and Fructose 2,6-bisphosphatase, favoring the Fructose 2,6-bisphosphatase. Decreasing cAMP (insulin) stimulates dephosphorylation, favoring PFK-2.

Fructose-2,6-bisphosphatase is strongly inhibited by fructose-6-phosphate.

Glucagon represses transcription of pyruvate kinase.

Glucagon activates transcription of phosphoenolpyruvate carboxykinase

Insulin represses transcription of phosphoenolpyruvate carboxykinase..

See also: Reactions and Enzymes of Glycolysis