A patient presents with dizziness, fatigue and tremors. A finger stick test indicates blood glucose of 36mmol/L. Of the allosteric activators of glycolysis in the liver, which of the following is the most important in maintaining a normal blood glucose level?
C. Fructose 2, 6 bisphosphate
E. Acetyl Co A
The correct answer is- C- Fructose 2,6 bisphosphate
Generally, enzymes that catalyze essentially irreversible steps in metabolic pathways are potential sites for regulatory control. Although most of the reactions of glycolysis are reversible, three are markedly exergonic and must therefore be considered physiologically irreversible. The enzymes responsible for catalyzing these three steps, hexokinase (or glucokinase) for step 1, phosphofructokinase for step 3, and pyruvate kinase for step 10, are the primary steps for allosteric enzyme regulation.
Phosphofructokinase is the “valve” controlling the rate of glycolysis.
Why is phosphofructokinase rather than hexokinase the pacemaker of glycolysis? The reason becomes evident on noting that glucose 6-phosphate is not solely a glycolytic intermediate. Glucose 6-phosphate can also be converted into glycogen or it can be oxidized by the pentose phosphate pathway to form NADPH. The first irreversible reaction unique to the glycolytic pathway, the committed step, is the phosphorylation of fructose 6- phosphate to fructose 1,6-bisphosphate. Thus, it is highly appropriate for phosphofructokinase to be the primary control site in glycolysis.
Fructose-2,6-bisphosphate increases the net flow of glucose through glycolysis by stimulating phosphofructokinase and, by inhibiting fructose-1,6-bisphosphatase, the enzyme that catalyzes this reaction in the opposite direction.
ATP is an allosteric inhibitor of this enzyme. In the presence of high ATP concentrations, the Km for fructose-6-phosphate is increased, glycolysis thus “turns off.” ATP elicits this effect by binding to a specific regulatory site that is distinct from the catalytic site. AMP reverses 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.
Citrate inhibits phosphofructokinase by enhancing the inhibitory effect of ATP. Inhibition of glycolysis by citrate ensures that glucose will not be committed to these activities if the citric acid cycle is already saturated.
Glucose-6-phosphate is a product of hexokinase catalyzed first reaction of glycolysis. The Hexokinase enzyme is allosterically inhibited by the product, glucose-6-phosphate.
Acetyl co A is an inhibitor of pyruvate kinase, thus it inhibits glycolysis. Pyruvate kinase is activated by AMP and fructose-1,6-bisphosphate and inhibited by ATP, acetyl-CoA, and alanine.
Role of 2,6 bisphosphate
Two enzymes regulate its concentration by phosphorylating fructose 6-phosphate and dephosphorylating fructose 2,6- bisphosphate.
Synthesis of fructose2,6-bisphosphate
Fructose 2,6-bisphosphate is formed in a reaction catalyzed by phosphofructokinase 2 (PFK2), a different enzyme from phosphofructokinase.
Degradation of Fructose 2,6-bisphosphate
Fructose 2,6-bisphosphate is hydrolyzed to fructose 6-phosphate by a specific phosphatase, fructose bisphosphatase 2 (FBPase2).
Regulation of concentration of Fructose 2,6-bisphosphate
The striking finding is that both PFK2 and FBPase2 are present in a single 55–kd polypeptide chain (figure-1).This bifunctional enzyme contains an N-terminal regulatory domain, followed by a kinase domain and a phosphatase domain. The bifunctional enzyme itself probably arose by the fusion of genes encoding the kinase and phosphatase domains.
Figure –1– showing the orientation of functional domains of bifunctional enzyme
In the liver, the concentration of fructose 6-phosphate rises when blood-glucose concentration is high, and the abundance of fructose 6-phosphate accelerates the synthesis of F- 2,6-BP. (Figure-2) Hence, an abundance of fructose 6–phosphate leads to a higher concentration of F–2,6–BP, which in turn stimulates phosphofructokinase. The product of PFK-1 catalyzed reaction Fr 1,6 bisphosphate further stimulates pyruvate kinase enzyme. Such a process is called feed forward stimulation.
The activities of PFK2 and FBPase2 are reciprocally controlled by phosphorylation of a single serine residue. When glucose is scarce, a rise in the blood level of the hormone glucagon triggers a cyclic AMP cascade, leading to the phosphorylation of this bifunctional enzyme by protein kinase A. This covalent modification activates FBPase2 and inhibits PFK2, lowering the level of F-2,6-BP. Thus, glucose metabolism by the liver is curtailed (figure-2).
Conversely, when glucose is abundant, the enzyme loses its attached phosphate group. This covalent modification activates PFK2 and inhibits FBPase2, raising the level of F-2,6-BP and accelerating glycolysis.
Thus, when glucose is abundant as during fed state, glycolysis is stimulated and when glucose is limiting as during fasting or starvation glycolysis is inhibited. These effects are brought about by hormones affecting the concentration of fructose 2,6 bisphosphate through action on the bifunctional enzymes fructose 2,6 bisphosphatase and PFK-2.
Figure- 2-showing the role of fructose 2,6 bisphosphate in the regulation of PFK-1 enzyme of Glycolysis
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