Phosphofructokinase glycolysis regulation

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... 

Storey, K.B. Hochachka, P.W. (1974). Activation of muscle glycolysis A role for creatine phosphate in phosphofructokinase regulation. FEES Lett. 46, 337-339. 

This reaction is followed by another phosphorylation with ATP catalyzed by the enzyme phosphofructoki-nase (phosphofructokinase-1), forming fructose 1,6-bisphosphate. The phosphofructokinase reaction may be considered to be functionally irreversible under physiologic conditions it is both inducible and subject to allosteric regulation and has a major role in regulating the rate of glycolysis. Fructose 1,6-bisphosphate is cleaved by aldolase (fructose 1,6-bisphosphate aldolase) into two triose phosphates, glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Glyceraldehyde 3-phosphate and dihydroxyacetone phosphate are inter-converted by the enzyme phosphotriose isomerase. 

The increase in proton concentration in the muscle decreases the activities of two key enzymes, which regulate the flux through glycolysis phosphorylase and phosphofructokinase (Chapter 13) (Figure 6.7). 

Phosphofructokinase-1 is a regulatory enzyme (Chapter 6), one of the most complex known. It is the major point of regulation in glycolysis. The activity of PFK-1 is increased whenever the cell s ATP supply is depleted or when the ATP breakdown products, ADP and AMP (particularly the latter), are in excess. The enzyme is inhibited whenever the cell has ample ATP and is well supplied by other fuels such as fatty acids. In some organisms, fructose 2,6-bisphosphate (not to be confused with the PFK-1 reaction product, fructose 1,6-bisphosphate) is a potent allosteric activator of PFK-1. The regulation of this step in glycolysis is discussed in greater detail in Chapter 15. 

The reaction catalyzed by phosphofructokinase A. is activated by high concentrations of ATP and citrate. B. uses fructose 1-phosphate as substrate. C. is the regulated reaction of the glycolytic pathway. D. is near equilibrium in most tissues. E. is inhibited by fructose 2,6-bisphosphate. Correct answer = C. Phosphofructokinase is the pace-setting enzyme of glycolysis. It is inhibited by ATP and citrate, uses fructose 6-phosphate as substrate, and catalyzes a reaction that is far from equilibrium. The reaction is activated by fructose 2,6-bisphosphate. 

Glycolysis and gluconeogenesis. The highly regulated enzymes phosphofructokinase and fructose... 

It is now generally recognized that an important site of regulation of both glycolysis and gluconeogenesis is at the level of fructose diphosphate formation and hydrolysis (10). In the direction of glycolysis, the activity of phosphofructokinase is inhibited by ATP and citrate, and this inhibition is reversed by AMP (11). The discovery that FDPase... 

Phosphofructokinase and the other enzymes that regulate pseudocycles I, IL and III of glycolysis are influenced by both intracellular and extracellular signals. We consider some of the intracellular signals first. 

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. 

In addition to its importance in providing cytosolic acetyl-CoA and NADPH, citrate also serves as a major regulator of the rate of fatty acid synthesis. As we shall see (chapter 18) citrate is a strong positive modifier of the first reaction in fatty acid synthesis. It should be remembered (see chapter 12) that citrate also is a negative modifier of phosphofructokinase and thereby exerts a negative effect on glycolysis, which also occurs in the cytosol. 

Newsholme E. A., Sugden P. H. and Williams T. (1977) Effect of citrate on the activities of 6-phosphofructokinase from nervous and muscle tissues from different animals and its relationships to the regulation of glycolysis. Biochem. J. 166, 123-129. 

The most important control step of glycolysis is the irreversible reaction catalyzed by phosphofructokinase (PFK). The enzyme is regulated in several ways ... 

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