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Isoforms of PFK-2 and FBP-2 have been identified in different tissues. They differ

in their affinity (Ks) for their substrates and in their sensitivity to regulation by

phosphorylation/dephosphorylation. This rationalises the observation that the fine

mechanistic detail for the control of PFK activity and hence of the regulation of

glycolysis varies between different mammalian tissues.

In general, substrate cycles are an important means by which the activity of meta-

bolic pathways is controlled. They operate at the expense of energy (ATP) and may

simultaneously determine the relative importance of branch points in bidirectional

pathways.

15.5.3 Signal amplification

The substrate cycles discussed above enabled opposing pathways to be controlled and

small changes in the concentration of ATP to be amplified in terms of concomitant

changes in AMP that is a key allosteric regulator of rate-limiting enzymes. This concept

ofamplificationis important in the fine control of metabolic pathways and in the

Fructose-6-phosphate

Fructose-1,6-bisphosphate

Fructose-2,6-bisphosphate

PFK

FBP-2

FBP

PFK-2

AMP +

F26BP +

ATP –

Ca2+ –

Citrate –

cAMP-DPK +

Phosphatase –

AMP –

ATP +

F26BP –

cAMP-DPK –

Phosphatase +

Fig. 15.14Regulation of phosphofructokinase (PFK). Two substrate cycles each centred on fructose-6-

phosphate are involved. Different enzymes promote the forward and reverse reactions of each cycle so that all

reactions are exergonic (negative free energy changes). Each enzyme is subject to activation (þ) or inhibition

() either by allosteric effectors or by phosphorylation/dephosphorylation (cAMP-DPK, cyclic AMP-dependent

protein kinase). The importance of each regulatory mechanism varies between organisms and between

different tissues in a given organism.

619 15.5 Control of enzyme activity