Fructose-1,6-bisphosphatase-phosphofructokinase cycle

Substrate cycles generate heat, a property that is apparently put to good use by cold bumblebees whose thoracic temperature must reach at least 30°C before they can fly. The insects apparently use the fructose bisphosphatase-phosphofructokinase substrate cycle (Fig. 11-2, steps b and c) to warm their flight muscles.268 It probably helps to keep us warm, too. 

Figure 3.30 The fructose 6-phosphate/fructose 1,6-bisphosphate cycle. The forward reaction is catalysed by the enzyme phosphofructokinase, the reverse reaction by fructose bisphosphatase.

It has been proposed that the substrate cycle involving phosphofructokinase and fructose bisphosphatase is used by bumblebees to warm their flight muscles to 30°C before flight begins. 

Does the existence of the phosphofructokinase-fructose-1,6-bisphosphatase substrate cycle have any energetic disadvantages ... 

A substrate cycle is produced by the simultaneous operation of opposing but chemically distinct reactions (32). For example, the enzymes 6-phosphofructokinase (PFK) and fructose bisphosphatase (FBPase) catalyze nonequilibrium and opposing reactions so that they can produce the fructose 6-phosphate/fructose bisphosphate substrate cycle, as follows ... 

If fructose-1,6-bisphosphatase and phosphofructokinase acted simultaneously, they would constitute a substrate cycle in which fructose-1,6-bisphosphate and fructose-6-phosphate became interconverted with net consumption of ATP ... 

FIGURE 15-21 Regulation of fructose 1,6-bisphosphatase-1 (FBPase-1) and phosphofructokinase-1 (PFK-1). The important role of fructose 2,6-bisphosphate in the regulation of this substrate cycle is detailed in subsequent figures. 

The effects of ATP, AMP, and fructose 2,6-bisphos-phate on phosphofructokinase have been discussed in Chapter 11, Section C. Fructose 2,6-P2 is a potent allosteric activator of phosphofructokinase and a strong competitive inhibitor of fructose 1,6-bisphosphatase (Fig. 11-2). It is formed from fructose 6-P and ATP by the 90-kDa bifunctional phosphofructo-2-kinase/ fructose 2,6-bisphosphatase. Thus, the same protein forms and destroys this allosteric effector. Since the bifunctional enzyme is present in very small amounts, the rate of ATP destruction from the substrate cycling is small. 

In glycolysis, the enzymes phosphofructokinase (PFK) and fructose 1,6-bisphosphatase (FBP) form a substrate cycle ... 

Certain allosteric effectors have reciprocal effects on enzymes that catalyse directly opposite reactions. For example, AMP activates phosphofructokinase and hence promotes glycolysis and the formation of ATP, while at the same time it inhibits liver fructose 1,6-bisphosphatase, thereby suppressing gluconeogenesis and this form of ATP expenditure. This is one means by which futile cycling may be prevented. 

A priori it would seem sensible that the activities of opposing enzymes such as phosphofructokinase and fructose 1,6-bisphosphatase should be regulated in such a way that one is active and the other inactive at any time. If both were active at the same time then there would be cycling between fructose 6-phosphate and fructose 1,6-bisphosphate, with hydrolysis of ATP - a so-called futile cycle. 

Substrate cycling also provides a means of increasing the sensitivity and speed of metabolic regulation. The increased rate of glycolysis in response to a need for ATP for muscle contraction would imply a more or less instantaneous 1000-fold increase in phosphofructokinase activity if phosphofructokinase were inactive and fructose 1,6-bisphosphatase active. If there is moderate activity of phosphofructokinase, but greater activity of fructose 1,6-bisphosphatase, so that the metabolic flux is in the direction of gluconeogenesis, then a more modest increase in phosphofructokinase activity and decrease in fructose 1,6-bisphosphatase activity will achieve the same reversal of the direction of flux. 

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