Reciprocal Regulation

Gluconeogenesis synthesizes glucose, whereas glycolysis catabolizes it, both occurring in the same cellular location, the cytoplasm. Because gluconeogenesis uses more ATP and GTP energy than glycolysis generates, it would be counterproductive for the cell to operate both pathways at the same time. The net product of these two pathways would be a futile cycle in which large quantities of ATP and GTP energy would be lost. The term "futile cycle" is used to describe situations in which catabolic and biosynthetic pathways such as these are occurring at the same time.

The simplest mechanism for regulating opposing pathways is in a reciprocal fashion. That is, intracellular conditions that activate one pathway simultaneously inhibit the other. Though this can be accomplished in a variety of ways, the most common one is allosteric regulation of key control enzymes for the two pathways. In Figure 16.6, for example, which illustrates the reciprocal regulatory mechanisms of glycolysis and gluconeogenesis, the key control points are the interconversions of glucose and glucose-6-phosphate, fructose-6-phosphate and fructose-1,6-bisphosphate, and phosphoenolpyruvate and pyruvate. In both pathways, these are the most strongly exergonic interconversions and thus, the ones that most distinctly differentiate glycolysis from gluconeogenesis.

Reciprocal regulation of the glycolysis and gluconeogenesis pathways is related in large part to the adenylate energy charge. 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 ATP levels remain sufficiently high.

Other reciprocal regulators of glycolysis and gluconeogenesis are fructose-2,6-bisphosphate and acetyl-CoA. See Figure 16.7 for additional details about the reciprocal regulatory mechanisms of action of fructose-2,6-bisphophate.

Acetyl-CoA is a reciprocal regulator because it activates pyruvate carboxylase (the enzyme that converts pyruvate to oxaloacetate in the two-step conversion of pyruvate to phosphoenolpyruvate in gluconeogenesis) and it inhibits pyruvate kinase (the enzyme that converts PEP to pyruvate in glycolysis). Thus, rising levels of acetyl-CoA may signal that adequate substrates are available to provide energy through the citric acid cycle and that more carbon can be shuttled into gluconeogenesis and ultimately stored as glycogen.

See also: Regulation of Gluconeogenesis, Reciprocal Regulation of Glycogen Biosynthesis and Mobilization, Fructose-2,6-Bisphosphate in Gluconeogenesis Regulation