Fructose 2, 6-bisphosphate is a potent regulator of glycolysis and gluconeogenesis

Fructose 2, 6-bisphosphate is a potent regulator of glycolysis and gluconeogenesis

Allosteric activator of PFK1: Stimulates glycolysis

When fructose 2, 6-bisphosphate binds to its allosteric site on PFK-1, it increases that enzyme’s affinity for its substrate, fructose 6-phosphate, and reduces its affinity for the allosteric inhibitors ATP and citrate.

Allosteric inhibitor of Fructose-1, 6-bisphosphatase (FBPase1): Inhibits gluconeogenesis

  • Insulin and glucagon controls the balance between glycolysis and gluconeogenesis via Fructose 2, 6 bisphosphate
  • The presence of F26BP in the cell is a glycolytic signal, which means it will push the cell to do more glycolysis and less gluconeogenesis.
  • When F26BP levels drop, the cell will do more gluconeogenesis and less glycolysis
Figure 1

Synthesis of Fructose 2, 6 bisphosphate

  • It is formed by phosphorylation of fructose 6-phosphate catalyzed by phosphofructokinase- 2 (PFK-2)

Degradation of Fructose 2, 6 bisphosphate

  • It is hydrolysed to fructose 6 phosphate catalysed by fructose 2, 6- bisphosphatase (FBPase-2).

The cellular concentration of the regulator fructose 2, 6-bisphosphate (F26BP) is determined by the rates of its synthesis by phosphofructokinase- 2 (PFK-2) and breakdown by fructose 2, 6-bisphosphatase (FBPase-2) which in turn controlled by hormones.

Figure 2: Synthesis and degradation of Fructose 2, 6 bisphosphate

Feature of PFK2/FBPase2 bifunctional protein

  •  Bifunctional enzyme contains an N-terminal regulatory domain, followed by a kinase domain and a phosphatase domain (PFK-2 and FBPase-2 are two distinct enzymatic activities of a single, bifunctional protein)
  •  The activities of PFK2 and FBPase2 are reciprocally controlled by phosphorylation of a single serine residue.

 Phosphorylated form of the enzyme: Fructose 2, 6 bisphosphatase activity (decreases the level of fructose-2, 6-bisphosphate).

Dephosphorylated form of the enzyme: PFK2 activity (It acts as the kinase and therefore raises the level of fructose-2, 6-bisphosphate).

PFK2 and FBPase2 are reciprocally activated and inactivated because they catalyse the opposite reactions.

Regulation of Phosphofructokinase-2/Fructose-2, 6-bisphosphatase in Liver and Muscle

Regulation in liver: insulin activates glycolysis, epinephrine and glucagon inhibits glycolysis

How glucagon hormone acts?

When the blood glucose level decreases (Eg: Fasting), the hormone glucagon signals the liver to produce and release more glucose and to stop consuming it for its own needs. One source of glucose is glycogen stored in the liver and another source is gluconeogenesis.

  • Glucagon stimulates the adenylyl cyclase of liver to synthesize cAMP from ATP.
  • Then cAMP activates cAMP-dependent protein kinase (PKA)
  • This kinase phosphorylates the PFK-2/FBPase-2 enzyme at an NH2-terminal Ser residue with ATP.
  • Phosphorylation of this protein enhances its FBPase-2 activity and inhibits its PFK-2 activity.
  • Glucagon thereby lowers the cellular level of fructose 2, 6-bisphosphate.
  • This leads to the inhibition of glycolysis and stimulation of gluconeogenesis.
  • The resulting production of more glucose enables the liver to replenish blood glucose in response to glucagon.

How insulin hormone acts?

 When blood glucose level increases, insulin signals a cell to do more glycolysis and less gluconeogenesis.

  • Insulin stimulates the activity of a phosphoprotein phosphatase that catalyzes removal of the phosphoryl group from the bifunctional protein PFK-2/FBPase-2.
  • Dephosphorylation of the bifunctional protein leads to the activation of PFK-2 activity which inturn increasing the level of fructose 2, 6-bisphosphate.
  • Fructose 2, 6 bisphosphate then stimulates PFK1, stimulating glycolysis and inhibiting Gluconeogenesis
Figure 3: Regulation of enzyme activity (PFK2 and FBPase2) of bifunctional protein by insulin and glucagon in a reciprocal fashion

Regulation in muscles: Insulin and epinephrine activates glycolysis

What is feedforward stimulation?

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. Hence, an abundance of fructose 6-phosphate leads to a higher concentration of F-2, 6-BP, which in turn stimulates phosphofructokinase. Such a process is called feedforward stimulation.

Point to remember

Although structurally related to fructose 1, 6- bisphosphate, fructose 2, 6-bisphosphate is not an intermediate in gluconeogenesis or glycolysis; it is a regulator whose cellular level reflects the level of glucagon in the blood, which rises when blood glucose falls.

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