Phosphofructokinase, regulation

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

Pemtothenic Acid, 230 Papain, 429 Pectins, 63 Peptidases, 428 Peptides, 148 Phosphatidyl choline, 82 Phosphatidyl ethanolamine, 83 Phosphatidyl glycerol, 84 Phosphofructokinase Regulation, 281 Phosphoglycerate Kinase, 286 Phosphoglycerate Mutase, 286 Phosphoproteins, 151 Photorespiration, 484 Photosynthesis, 471 Pih, 10 Plant CeU, 16... 

Phosphofructokinase. Regulation with respect to ATP is the same in the liver as in muscle. Low pH is not a metabolic signal for the liver enzyme, because lactate is not normally produced in the liver. Indeed, as we will see, lactate is converted into glucose in the liver. 

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... 

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). 

Figure 16.1 The glucose/fatty add cycle. The dotted Lines represent regulation. Glucose in adipose tissue produces glycerol 3-phosphate which enhances esterification of fatty acids, so that less are available for release. The effect is, therefore, tantamount to inhibition of lipolysis. Fatty acid oxidation inhibits pyruvate dehydrogenase, phosphofructokinase and glucose transport in muscle (Chapters 6 and 7) (Randle et al. 1963).

Structural Basis of Allosteric Regulation on the Example of Phosphofructokinase... 

Based on high resolution crystal structures, detailed understanding of the molecular principles of allosteric regulation for several enzyme systems could be gleamed. One of the best studied examples is that of phosphofructokinase from Bac. stearothermophilus (Schirmer and Evans, 1990). 

Fig. 2.6. Regulation of Phosphofructokinase from Bacillus stearothermophilus. The tetrameric phosphofructokinase is aUostericaUy regulated by ADP, Frc-6-phosphate, and phosphoenolpyruvate (PEP). The binding of ADP and Frc-6-phosphate converts the enzyme into the active R state. PEP binds to the T state and inhibits phosphofructokinase. The circles represent the R state, and the squares represent the T state of the enzyme.

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. 

FIGURE 15-21 Regulation of fructose 1,6-bisphosphatase-1 (FBPase-1) and phosphofructokinase-1 (PFK-1). The important role of fructose 2,6-bisphosphate in the regulation of this substrate cycle is detailed in subsequent figures. 

Three glycolytic enzymes are subject to allosteric regulation hexoldnase IV, phosphofructokinase-1 (PFK-1), and pyruvate kinase. 

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