Principles of Biochemistry, Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Biosynthesis of Carbohydrates in Animal Tissues
Futile Cycles in Carbohydrate Metabolism

A careful reader examining the pathways of Glycolysis and Gluconeogenesis shown in Fig. 20-2 is bound to ask a very difficult question. Along these oppositely directed metabolic pathways between glucose and Pyruvate, there are three points where the catabolic enzymatic reactions are replaced in the anabolic pathway by alternative, bypass reactions. Phosphofructokinase, for example, catalyzes the phosphorylation of fructose-6-phosphate at the expense of ATP, whereas in gluconeogenesis its counterpart is fructose diphosphatase, which catalyzes the bypass reaction—the Hydrolysis of fructose-1,6-diphosphate to yield fructose-6-phosphate. Let us write down these two opposing reactions:

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Summing them up, we obtain the reaction

in which, as we can see, energy is wasted because the net hydrolysis of ATP is not accompanied in this case by any actual metabolic work. Clearly, if these two reactions were to proceed simultaneously and at a high rate within the same Cell, it could result in massive energy losses, dissipating as heat. Such a cycle, which results in The breakdown of ATP, has been termed a futile cycle. A similar futile cycle could obviously involve such a pair of corresponding Enzymes as hexokinase and glucose-6-phosphatase

Under normal conditions, futile cycles probably do not occur, as reciprocal regulatory mechanisms prevent their emergence. Whenever Catabolism predominates—that is, when the net flux is directed toward glycolysis—fructose diphosphatase activity is switched off. Conversely, when the net flux is directed toward gluconeogenesis, phosphofructokinase is turned off.

Recent studies have shown, however, that futile cycles can sometimes occur under physiological conditions as well, serving a very definite biological purpose: heat production. A fascinating example of such a futile cycle has been discovered in certain insects. In cold weather, a bumblebee cannot fly until it warms up its "engine"; its flight Muscle Temperature must rise to roughly 30˚C and be maintained at this level through a futile cycle involving fructose-6-phosphate and fructose-1,6-diphosphate, followed by the hydrolysis of ATP to serve as a heat source. It is also believed that heat-generating futile cycles may occur in some animals awakening from hibernation—that is, during a period when the animal's body temperature is well below normal.