Glut2

Plasma ' membrane

Glucose 6-phosphate

Fructose 6-phosphate

Plasma ' membrane

Glucose 6-phosphate

Fructose 6-phosphate

FIGURE 15-17 Regulation of hexokinase IV (glucokinase) by sequestration in the nucleus. The protein inhibitor of hexokinase IV is a nuclear binding protein that draws hexokinase IV into the nucleus when the fructose 6-Ophosphate concentration in liver is high and releases it to the cytosol when the glucose concentration is high.

FIGURE 15-17 Regulation of hexokinase IV (glucokinase) by sequestration in the nucleus. The protein inhibitor of hexokinase IV is a nuclear binding protein that draws hexokinase IV into the nucleus when the fructose 6-Ophosphate concentration in liver is high and releases it to the cytosol when the glucose concentration is high.

complex enzyme has several regulatory sites at which allosteric activators or inhibitors bind.

ATP is not only a substrate for PFK-1 but also an end product of the glycolytic pathway. When high cellular [ATP] signals that ATP is being produced faster than it is being consumed, ATP inhibits PFK-1 by bind ing to an allosteric site and lowering the affinity of the enzyme for fructose 6-phosphate (Fig. 15-18). ADP and AMP, which increase in concentration as consumption of ATP outpaces production, act allosterically to relieve this inhibition by ATP. These effects combine to produce higher enzyme activity when ADP or AMP accumulates and lower activity when ATP accumulates.

Citrate (the ionized form of citric acid), a key intermediate in the aerobic oxidation of pyruvate, fatty acids, and amino acids, also serves as an allosteric regulator of PFK-1; high citrate concentration increases the inhibitory effect of ATP, further reducing the flow of glucose through glycolysis. In this case, as in several others encountered later, citrate serves as an intracellular signal that the cell is meeting its current needs for energy-yielding metabolism by the oxidation of fats and proteins.

The most significant allosteric regulator of PFK-1 is fructose 2,6-bisphosphate, which strongly activates the enzyme. We return to this role of fructose 2,6-bisphosphate later.

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