What Effects Might Inhibit Glycolysis?

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Glycolysis is a process in which glucose is converted into pyruvate or lactate depending on whether it occurs under aerobic or anaerobic conditions. The regulation of this pathway occurs at three key points where the enzyme reactions involved are irreversible. These three enzymes are hexokinase, phosphofructokinase and pyruvate kinase. Inhibition of glycolysis is a mechanism to conserve energy by preventing the breakdown of adenosine triphosphate.

Buildup of Glucose-6-Phosphate

  • Hexokinase enzyme catalyzes the first step of glycolysis, in which glucose gets converted into glucose-6-phosphate. High concentrations of this product inhibit the enzyme's activity. When it accumulates, the glucose-6-phosphate competes with the substrate glucose to bind at the enzyme's active site, as well as another allosteric site. This binding inhibits the action of hexokinase.

Action of Glucokinase Regulatory Protein

  • In the liver, the conversion of glucose to glucose-6-phosphate occurs by action of a hexokinase variant called glucokinase. Unlike hexokinase, glucokinase is unaffected by concentrations of glucose-6-phosphate and therefore does not get inhibited by it. The action of glucokinase is modulated by the presence of a protein called glucokinase regulatory protein (GKRP). The binding of GKRP to glucokinase enzyme inhibits glycolysis in the liver.

Accumulation of ATP

  • In the glycolysis cycle, the reaction catalyzed by phosphofructokinase is the rate-limiting step. This enzyme catalyzes the phosphorylation of fructose-6-phosphate by ATP to produce fructose-1,6-biphosphate. In conditions when there is a high concentration of ATP, there is no further requirement for glycolysis. This ATP binds at an allosteric site on the phosphofructokinase enzyme and causes a change in its conformation. This conformational change prevents the binding of the substrate fructose-6-phosphate and thus inhibits the activity of the enzyme which in turn inhibits glycolysis.

Inhibition of Pyruvate Kinase

  • Pyruvate kinase enzyme is the third site of regulation of glycolysis. The activity of this enzyme is inhibited by presence of high concentrations of ATP. The presence of alanine which is biosynthesized from pyruvate also acts as an inhibitory factor. Both ATP and alanine bind to an allosteric site on the pyruvate kinase enzyme and bring about a reduction of its activity. When blood sugar levels drop, phosphorylation of the pyruvate kinase enzyme occurs, which makes the enzyme inactive, inhibiting glycolysis.

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