One rate-limiting step of glycolysis is the conversion of Fructose-6-Phosphate (Fruc-6-P) to Fructose-1,6-Bisphosphate (Fruc-1,6-BP), catalysed by Phosphofructokinase 1 (PFK 1). The reaction involves hydrolysing one ATP to ADP.

The reverse reaction of gluconeogenesis is catalysed by Fructose-Bisphosphatase (FBP). This reaction uses 1 H2O for hydrolysis and yields 1 phosphate (Pi).

One would expect the cell to be utilising only one of the two reactions at any one time, either to break down glucose or to generate it. However, the case is commonly that both reactions are taking place simultaneously in an equilibrium [ref 'Biochemistry', Voet & Voet, 4th ed., 628-629 (Section 17-4-F-f,g,h,(i))], cycling Fruc-1,6-BP to no apparent benefit, at the expense of valuable ATP.

What is the purpose of such futile cycles?

  • $\begingroup$ I'd like to note that I have known the reason before, and I'm almost certain I have it somewhere in my material from last year - I just realised that I couldn't explain it to someone right now and I believe this question would be a valuable addition to our site. I am currently busy, but will answer it myself once I am free (unless someone else does beforehand). $\endgroup$ – Armatus May 2 '13 at 23:10
  • $\begingroup$ gluconeogenesis is not continuously happening and is tightly regulated at the step of FBP. Therefore there is no continuous futile cycle $\endgroup$ – WYSIWYG May 3 '13 at 4:20
  • $\begingroup$ PFK is not rate-limiting, this has been shown many time. It can't be since it is regulated. $\endgroup$ – rhody Oct 29 '13 at 1:23
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    $\begingroup$ In some organisms such as bubble bees, futile cyclying in muscle is thought to generate heat in flight muscles. Also a futile cycled system can act as a flux amplifier. $\endgroup$ – rhody Oct 29 '13 at 1:24
  • $\begingroup$ This question, like many others on metabolism, is meaningless in referring to "the cell" without specifying what cell one is talking about because the poster does not understand that different animal tissues have different metabolism which is different again from bacteria. Unsupported as it is by any references it should have been clarified when it was asked. Let's just bury it now. $\endgroup$ – David Aug 29 '17 at 19:27

As far as I am aware there are various regulatory mechanisms (allosteric regulation, hormonal control) in place to minimise futile cycling by ensuring that phosphofructokinase (glycolysis) and fructose 1,6 bisphosphatase (gluconeogenesis) are not both active at the same time.

See this Wikipedia article for a starting point.

The precise regulation of PFK1 prevents glycolysis and gluconeogenesis from occurring simultaneously. However, there is substrate cycling between F6P and F-1,6-BP. Fructose-1,6-bisphosphatase (FBPase) catalyzes the hydrolysis of F-1,6-BP back to F6P, the reverse reaction catalyzed by PFK1. There is a small amount of FBPase activity during glycolysis and some PFK1 activity during gluconeogenesis. This cycle allows for the amplification of metabolic signals as well as the generation of heat by ATP hydrolysis.

The last two sentences of the quotation are probably what you remember reading about. There is a theory that having some cycling provides an element of regulatory responsiveness. See here for example. I'm not enough of a mathematician to explain this idea well.

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    $\begingroup$ You don't need math to understand it. Let's assume the cycling rate is 100 but the net flux is 10. If I increase the forward cycle rate by 10% then the net rate increases 100% (assuming the back rate doesn't absorb all your increase). This is actually a well known effect and was first described in the 1970s by Newsholme. $\endgroup$ – rhody Apr 9 '18 at 23:59

Phosphofructokinase 1 (PFK 1) is not rate-limiting, its flux control coefficient when measured is invariably small. The fact that textbooks keep suggesting the PFK is rate-limting is just a textbook myth.

Here is a selection of papers that support the observation that the flux control coefficient for PFK is invariably small. There are also very strong theoretical arguments that are consistent with these observations.

  1. Heinisch J. Isolation and characterisation of the two structural genes coding for phosphofructokinase in yeast. Mol Gen Genet. 1986;202:75–82.

  2. Schaaff I, Heinisch J, Zimmermann FK. Overproduction of glycolytic enzymes in yeast. Yeast. 1989;5(4):285–290.

  3. Davies SE, Brindle KM. Effects of overexpression of phosphofructokinase on glycolysis in the yeast Saccharomyces cerevisiae. Biochemistry. 1992;31(19):4729–4735.

  4. Burrell MM, Mooney PJ, Blundy M, Carter D, Wilson F, Green J, et al. Genetic manipulation of 6-phosphofructokinase in potato tubers. Planta. 1994;194:95—–101.

  5. Thomas S, Mooney PJ, Burrell MM, et al. Metabolic control analysis of glycolysis in tuber tissue of potato (Solanum tuberosum): explanation for the low control coefficient of phosphofructokinase over respiratory flux. Biochemical Journal. 1997;322(1):119–127.

  6. Ruijter G, Panneman H, Visser J. Overexpression of phosphofructokinase and pyruvate kinase in citric acid-producing Aspergillus niger. Biochimica et Biophysica Acta (BBA)-General Subjects. 1997;1334(2):317–326.

  7. Muller S, Zimmermann FK, Boles E. Mutant studies of phosphofructo-2-kinases do not reveal an essential role of fructose-2, 6-bisphosphate in the regulation of carbon fluxes in yeast cells. Microbiology. 1997;143(9):3055–3061.

  8. Urbano AM, Gillham H, Groner Y, Brindle KM. Effects of overexpression of the liver subunit of 6- phosphofructo-1-kinase on the metabolism of a cultured mammalian cell line. Biochemical Journal. 2000;352(3):921–927.

  9. Marın-Hernandez A, Rodrıguez-Enrıquez S, Vital-Gonzalez PA, Flores-Rodrıguez FL, Macıas-Silva M, Sosa-Garrocho M, et al. Determining and understanding the control of glycolysis in fast-growth tumor cells. FEBS Journal. 2006;273(9):1975–1988.

  10. Moreno-Sanchez R, Marın-Hernandez A, Saavedra E, Pardo JP, Ralph SJ, Rodrıguez-Enrıquez S. Who controls the ATP supply in cancer cells? Biochemistry lessons to understand cancer energy metabolism. The international journal of biochemistry & cell biology. 2014;50:10–23.

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    $\begingroup$ You may be right, but how can we tell unless you cite evidence in support of your argument? Please read the help on how to answer questions properly. Until you elaborate I have voted your answer down. $\endgroup$ – David Aug 29 '17 at 7:14
  • $\begingroup$ You're right, I just updated the comment with citation support. $\endgroup$ – rhody Aug 30 '17 at 17:31
  • $\begingroup$ Ok, I've reversed my vote. Unfortunately biochemical metabolism isn't the strong suit of many people on this list and it's difficult to revive interest in an old question. But I look forward to your participation when new questions come up, after the summer perhaps. $\endgroup$ – David Aug 30 '17 at 18:02
  • $\begingroup$ I'll try an monitor this forum. $\endgroup$ – rhody Sep 2 '17 at 2:33
  • $\begingroup$ Thanks for making me aware of this, very interesting to find out this idea is backwards. The question wasn't specific to glycolysis though - unless this is actually the only such cycle. The answer I ticked still remains the most accurate answer. $\endgroup$ – Armatus Apr 8 '18 at 20:50

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