Question

What makes phosphofructokinase the key allosteric enzyme in glycolysis?

Answer 1

In metabolic pathways, enzymes catalyzing essentially irreversible reactions are potential sites of control. In glycolysis, the reactions catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase are virtually irreversible; hence, these enzymes would be expected to have regulatory as well as catalytic roles. In fact, each of them serves as a control site. Their activities are regulated by the reversible binding of allosteric effectors or by covalent modification. In addition, the amounts of these important enzymes are varied by the regulation of transcription to meet changing metabolic needs. The time required for reversible allosteric control, regulation by phosphorylation, and transcriptional control is typically in milliseconds, seconds, and hours, respectively.

Phosphofructokinase is the most important control element in the mammalian glycolytic pathway . High levels of ATP allosterically inhibit the enzyme in the liver (a 340-kd tetramer), thus lowering its affinity for fructose 6-phosphate. A high concentration of ATP converts the hyperbolic binding curve of fructose 6-phosphate into a sigmoidal one . ATP elicits this effect by binding to a specific regulatory site that is distinct from the catalytic site. AMPreverses the inhibitory action of ATP, and so the activity of the enzyme increases when the ATP/AMP ratio is lowered. In other words, glycolysis is stimulated as the energy charge falls. A fall in pH also inhibits phosphofructokinase activity. The inhibition of phosphofructokinase by H+ prevents excessive formation of lactic acid and a precipitous drop in blood pH (acidosis).