Nh

*These potentiate the inhibitory effect of ATP.

During contraction, ATP is hydrolysed to ADP + Pi. It is partially replenished by phosphocreatine (see Fig. 8.7). The following associated reactions occur:

Reaction Effect

ATP ^ ADP + Pi (associated with contraction) ATP 4-, Pi T

2ADP ^ ATP + AMP (adenylate kinase) AMP T

PCr, phosphocreatine; Cr, creatine; IMP, inosine monophosphate (a degradation product of AMP).

Thus, the changes in allosteric effectors all act to activate PFK. Substrate cycling

However, it is difficult to envisage that an enzyme can alter its activity by a factor of 1000 in one second or so. For this reason, it has been proposed that the sensitivity of control may be increased by the existence of a substrate cycle between fructose 6-phosphate (F 6-P) and fructose-1,6-bisphosphate (F 1,6-P2). The reverse reaction is catalysed by fructose-1,6-bisphosphatase (FBPase).

The concept may be illustrated as shown in Fig. 8.4.1.

In the top scheme ('resting'), the flux through PFK is 55 (arbitrary units) and the reverse flux 5, giving a net flux along the pathway of 50 arbitrary units. On the starting blocks (middle scheme), anticipation (perhaps mediated via stress hormones) leads to a 36-fold activation of PFK and a 390-fold activation of FBPase (these are reasonable changes since they need not be instantaneous). The net flux (50 units) along the pathway remains unchanged. On the starting gun, an almost instantaneous change of 25.5-fold activation of PFK and halving of FBPase activity leads to a 1000-fold change in net flux through the pathway. The numbers illustrate the potential for increased sensitivity of metabolic control arising through substrate cycling, but are not based on physiological measurements.

This box and Fig. 8.4.1 are based largely on Newsholme & Leech (1983) with permission from John Wiley & Sons Ltd; quantitative estimates of the extent of substrate cycling in vivo are given by Newsholme & Challis (1992).

Resting

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