Gluconeogenesis fructose 1,6-bisphosphate

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. 

For all of these reactions, the equilibrium is in the direction of glycolysis, because of the utilization of ATP in the reaction and the high ratio of ATP to ADP in the cell. The reactions of phosphofructokinase and hexokinase are reversed in gluconeogenesis by simple hydrolysis of fructose bisphosphate to fructose 6-phosphate plus phosphate (catalysed by fructose bisphosphatase) and of glucose 6-phosphate to glucose plus phosphate (catalysed by glucose 6-phosphatase). 

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-bisphosphatase, a regulatory enzyme of gluconeogenesis (Chapter 19), catalyzes the hydrolytic release of the phosphate on carbon 2 of fructose 2,6-bisphosphate. Figure 7-8 illustrates the roles of seven active site residues. Catalysis involves a catalytic triad of one Glu and two His residues and a covalent phos-phohistidyl intermediate. 

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

In liver, cAMP activates gluconeogenesis, but in muscle, it activates glycolysis. Let s do liver first, and the muscle answer will just be the opposite. So, we want to activate gluconeogenesis in liver in response to increased phosphorylation (increased levels of cAMP). Phosphorylation of our enzyme (PFK-2) must have an effect that is consistent with the activation of gluconeogenesis. If gluconeogenesis is on and glycolysis is off, the level of fructose 2,6-bisphosphate (an activator of glycolysis) must fall. If fructose 2,6-bisphosphate is to fall, the PFK-2 that synthesizes it must be made inactive. So, in liver, phosphorylation of PFK-2 must inactivate the enzyme. 

Fructose-1,6-bisphosphatase is an important rate-limiting step in gluconeogenesis. This gluconeogenic step antagonizes the opposite reaction that forms fructose-1, 6-bisphosphate from fmctose-6-phosphate and ATP... 

Figure 6.22 Major precursors for gluconeogenesis. FBP is fructose 1,6-bisphosphate.

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 (Fru-2,6-bP) plays an important part in carbohydrate metabolism. This metabolite is formed in small quantities from fructose 6-phosphate and has purely regulatory functions. It stimulates glycolysis by allosteric activation of phosphofructokinase and inhibits gluconeogenesis by inhibition of fructose 1,6-bisphosphatase. 

The second glycolytic reaction that cannot participate in gluconeogenesis is the phosphorylation of fructose 6-phosphateby PFK-1 (Table 14-2, step ). Because this reaction is highly exergonic and therefore irreversible in intact cells, the generation of fructose 6-phosphate from fructose 1,6-bisphosphate (Fig. 14-16) is catalyzed by a different enzyme, Mg2+-dependent fructose 1,6-bisphosphatase (FBPase-1), which promotes the essentially irreversible hydrolysis of the C-l phosphate (not phosphoiyl group transfer to ADP) ... 

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) ... 

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. At the physiological concentrations of its substrates ATP and fructose 6-phosphate and of its other positive and negative effectors (ATP, AMP, citrate), PFK-1 is virtually inactive in the absence of fructose 2,6-bisphosphate. Fructose 2,6-bisphosphate activates PFK-1 and stimulates glycolysis in liver and, at the same time, inhibits FBPase-1, thereby slowing gluconeogenesis. 

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). 

To limit futile cycling between glycolysis and gluconeogenesis, the two pathways are under reciprocal allosteric control, mainly achieved by the opposite effects of fructose 2,6-bisphosphate on PFK-1 and FBPase-1. 

---