Gluconeogenesis fructose-2,6-bisphosphate regulation

Glucagon and epinephrine also regulate pseudocycle II so as to stimulate gluconeogenesis while inhibiting glycolysis. They do this through a chain of reactions that results in a lowering of the concentration of the allosteric effector fructose-2,6-bisphosphate. This effector stimulates phosphofructokinase while it inhibits fructose bisphosphate phosphatase. 

See also Regulation of Gluconeogenesis, Fructose-2,6-Bisphosphate in Gluconeogenesis Regulation, Gluconeogenesis Enzymes, Glycolysis Enzymes, AMP... 

As described in Chapter 19, Emile Van Schaftingen and Henri-Gery Hers demonstrated in 1980 that fructose-2,6-bisphosphate is a potent stimulator of phosphofructokinase. Cognizant of the reciprocal nature of regulation in glycolysis and gluconeogenesis. Van Schaftingen and Hers also considered the... 

Fructose 2,6-Bisphosphate Plays a Unique Role in the Regulation of Glycolysis Gluconeogenesis in Liver... 

Fructose 2,6-bisphosphate is not a metabolic intermediate but an allosteric regulator. It has two important roles it increases the activity of PFK-1 but decreases the activity of fructose 1,6-bisphosphatase (FBPase). Consequently an increase in the concentration of fructose 2,6-bisphosphate favours glycolysis but restricts gluconeogenesis. 

Fructose 2,6-Bisphosphate Is a Potent Regulator of Glycolysis and Gluconeogenesis... 

The hormonal regulation of glycolysis and gluconeogenesis is mediated by fructose 2,6-bisphosphate, an allosteric effector for the enzymes PFK-1 and FBPase-1 (Fig. 15-22) ... 

Gluconeogenesis is regulated at the level of pyruvate carboxylase (which is activated by acetyl-CoA) and FBPase-1 (which is inhibited by fructose 2,6-bisphosphate and AMP). 

Figure 16.30. Reciprocal Regulation of Gluconeogenesis and Glycolysis in the Liver. The level of fructose 2,6-bisphosphate is high in the fed state and low in starvation. Another important control is the inhibition of pyruvate kinase by phosphorylation during starvation.

The most potent regulator of liver PFK-1 is fructose-2,6-bisphosphate, which relieves the inhibition of PFK-1 by ATP and lowers the Km for fructose-6-phosphate. Fructose-2,6-bisphosphate is a potent inhibitor of fructose-1,6-bisphosphatase (which is important in gluconeogenesis) and thus ensures the continuation of glycolysis. Metabolism of fructose-2,6-bisphosphate, its role as activator of PFK-1 and inhibitor of fructose-1,6-bisphosphatase, and its allosteric and hormonal regulation are discussed in Chapter 15. 

Regulation of liver 6-phosphofructokina.se and fructose-1,6-bisphosphatase. These multimodulated enzymes catalyze nonequilibrium reactions, the former in glycolysis and the latter in gluconeogenesis. Note the dual action of fructose-2,6-bisphosphate (F-2.6-BP), which activates phosphofnictokinase (PFK-1) and inactivates fructose-1,6-bisphosphatase. The activity of F-2.6-BP is under hormonal and substrate regulation (Figure 15-6). = positive effectors 0 = negative effectors. 

Phosphorylation is regulated by insulin and glucagon. Diabetes mellitus (in which the ratio of glucagon to insulin is increased) and glucagon therapy reduce the hepatic activity of PFK-2 and increase that of FBPase-2. The concentration of fructose-2,6-bisphosphate is thus reduced, thereby stimulating gluconeogenesis. 

D-Fructose 1,6-diphosphatase is a regulatory enzyme playing a key role in the control of gluconeogenesis. A number of mechanisms have been proposed for the regulation of D-fructose 1,6-diphosphatase activity, including allosteric control by AMP,396 inhibition by D-fructose 1,6-bisphosphate, ADP, or ATP, and modification of the sulfhydryl groups of the enzyme.397,398... 

F6P is a phosphorylated form of fructose commonly found in cells. F6P is an intermediate in glycolysis, gluconeogenesis, the pentose phosphate pathway, and the Calvin cycle. F6P is a substrate in biosynthesis of the important allosteric factor regulating glycolysis, fructose-2,6-bisphosphate and is also an important precursor of amino sugars (last enzyme below). 

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