Futile cycle

Futile cycle

A futile cycle, also known as a substrate cycle, occurs when two metabolic pathways run simultaneously in opposite directions and have no overall effect other than to dissipate energy in the form of heat.[1] For example, if glycolysis and gluconeogenesis were to be active at the same time, glucose would be converted to pyruvate by glycolysis and then converted back to glucose by gluconeogenesis, with an overall consumption of ATP.[2] Futile cycles may have a role in metabolic regulation, where a futile cycle would be a system oscillating between two states and very sensitive to small changes in the activity of any of the enzymes involved.[3] The cycle does generate heat, and may be used to maintain thermal homeostasis, for example in the brown adipose tissue of young mammals, or to generate heat rapidly, for example in insect flight muscles and in hibernating animals during periodical arousal from torpor. It has been reported that the glucose metabolism substrate cycle is not a futile cycle but a regulatory process. For example, when energy is suddenly needed, ATP is replaced by AMP, a much more reactive adenine.


The simultaneous carrying out of glycolysis and gluconeogenesis is an example of a futile cycle, represented by the following equation:

ATP + H_2 O {\rightleftharpoons} ADP + P_i + heat

For example, during glycolysis, fructose-6-phosphate is converted to fructose-1,6-bisphosphate in a reaction catalysed by the enzyme phosphofructokinase 1 (PFK-1).

ATP + fructose-6-phosphate Fructose-1,6-bisphosphate + ADP

But during gluconeogenesis (i.e. synthesis of glucose from pyruvate and other compounds) the reverse reaction takes place, being catalyzed by fructose-1,6-bisphosphatase (FBPase-1).

Fructose-1,6-bisphosphate + H2O fructose-6-phosphate + Pi

Giving an overall reaction of:

ATP + H2O ADP + Pi + Heat

That is, hydrolysis of ATP without any useful metabolic work being done. Clearly, if these two reactions were allowed to proceed simultaneously at a high rate in the same cell, a large amount of chemical energy would be dissipated as heat. This uneconomical process has therefore been called a futile cycle.[4]


  1. ^ Schwender J, Ohlrogge J, Shachar-Hill Y (2004). "Understanding flux in plant metabolic networks". Curr Opin Plant Biol 7 (3): 309–17.  
  2. ^ Boiteux A, Hess B (1981). "Design of glycolysis". Philos Trans R Soc Lond B Biol Sci 293 (1063): 5–22.  
  3. ^ Samoilov M, Plyasunov S, Arkin A (2005). "Stochastic amplification and signaling in enzymatic futile cycles through noise-induced bistability with oscillations". Proc Natl Acad Sci USA 102 (7): 2310–5.  
  4. ^ Nelson, D. L., Lehninger, A. L., & Cox, M. M. (2008). Lehninger principles of biochemistry (5th ed., pp. 582-583). New York: W.H. Freeman.

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