Gluconeogenesis Phosphofructokinase

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... 

Mechanism for Gluconeogenesis. Since the glycolysis involves three energetically irreversible steps at the pyruvate kinase, phosphofructokinase, and hexokinase levels, the production of glucose from simple noncarbohydrate materials, for example, pyruvate or lactate, by a reversal of glycolysis ( from bottom upwards ) is impossible. Therefore, indirect reaction routes are to be sought for. 

The pathway for gluconeogenesis is shown in Figures 6.23 and 6.24. Some of the reactions are catalysed by the glycolytic enzymes i.e. they are the near-equilibrium. The non-equilibrium reactions of glycolysis are those catalysed by hexokinase (or glucokinase, in the liver), phosphofructokinase and pyruvate kinase and, in order to reverse these steps, separate and distinct non-equilibrium reactions are required in the gluconeogenic pathway. These reactions are ... 

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. 

Phosphofructokinase-2/fructose 2,6-bisphosphatase LQRRRGSSIPQ Glycolysis/gluconeogenesis... 

Hydrolysis of fructose 1,6-bisphosphate by fructose 1,6-bispho -phatase bypasses the irreversible phosphofructokinase-1 reaction, and provides an energetically favorable pathway for the formation of fructose 6-phosphate (Figure 10.4). This reaction is an important regulatory site of gluconeogenesis. 

Fructose 1,6-bisphosphatase is inhibited by AMP—a compound that activates phosphofructokinase Elevated AMP thus stimulates path ways that oxidize nutrients to provide energy for the cell. [Note ATP and NADH, produced in large quantities during fasts by catalytic path ways, such as fatty acid oxidation, are required for gluconeogenesis.]... 

Allosteric changes usually involve rate-determining reactions. For example, glycolysis in the liver is stimulated following a meal by an increase in fructose 2,6-bisphosphate, an allosteric activator of phosphofructokinase (see p. 98). Gluconeogenesis is inhibited by fructose 2,6-bisphosphate, an inhibitor of fructose 1,6-bisphos-phatase (see p. 118). 

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... 

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. 

These considerations do not take into account the major glycolytic controls exerted by the hexokinase-phosphofructokinase system (230) but they do show that G-3PDH could act as a regulatory enzyme in response to the NAD+ NADH and ATP ADP X Pi ratios in the cell. These ratios in conjunction with appropriate substrate (i.e., G-3P, DPGA, and Pi) concentrations prime the enzyme for glycolysis or gluconeogenesis in accord with the particular environment and needs of the cell. 

Biotin acts to induce glucokinase, phosphofructokinase, and pyruvate kinase (key enzymes of glycolysis), phosphoenolpyruvate carboxykinase (a key enzyme of gluconeogenesis), and holocarboxylase synthetase, acting via a cell-surface receptor linked to formation of cGMP and increased activity of RNA polymerase. The activity of holocarboxylase synthetase (Section 11.2.2) falls in experimental biotin deficiency and increases with a parallel increase in... 

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