Glycolysis Allosteric regulation

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. 

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. 

Figure 9.24 Control of the oxaloacetate concentration and hence the flux through the cycle by pyruvate carboxylase. The activity of pyruvate carboxylase is increased by an increase in its substrate, pyruvate, and its allosteric regulator, acetyl-CoA. Regulation of the activity is important to increase the concentration of oxaloacetate which increases the flux through the cycle. An increase in the rate of glycolysis increases the concentration of pyruvate, and an increase in the rate of fatty acid oxidation increases that of acetyl-CoA. Both result in an increase in the concentration of oxaloacetate and hence in the flux through the cycle, providing coordination between the rates of glycolysis, fatty acid oxidation and the cycle.

Allosteric interactions. The flow of molecules in most metabolic pathways is determined primarily by the activities of certain enzymes rather than by the amount of substrate available. Enzymes that catalyze essentially irreversible reactions are likely control sites, and the first irreversible reaction in a pathway (the committed step) is nearly always tightly controlled. Enzymes catalyzing committed steps are allosterically regulated, as exemplified by phosphofructokinase in glycolysis and acetyl CoA carboxylase in fatty acid synthesis. Allosteric interactions enable such enzymes to rapidly detect diverse signals and to adjust their activity accordingly. 

The last enzyme in glycolysis, pyruvate kinase, is also subject to allosteric regulation. In this case, fructose-l,6-bisphosphate is the allosteric activator. It is interesting that fructose-l,6-bisphosphate is the product of the reaction catalyzed by phosphofructokinase. Thus, activation of phosphofructokinase results in the activation of pyruvate kinase. This is an example of feedforward activation because the product of an earlier reaction causes activation of an enzyme later in the pathway... 

Glycolysis is tightly regulated in coordination with other energy-yielding pathways to assure a steady supply of ATP. Hexokinase, PFK-1, and pyruvate kinase are all subject to allosteric regulation that controls the flow of carbon through the pathway and maintains constant levels of metabolic intermediates. 

F2,6BP is one of the most important compounds involved in allosteric regulation of glycolysis and gluconeogenesis. 

PFK2 catalyzes formation of the compound fimctose-2,6-bisphosphate (F2,6BP) by transferring a phosphate from ATP onto position 2 of fructose-6-phosphate (F6P) (Figure 16.7). F2,6BP is the most important allosteric regulator of glycolysis and gluconeogenesis and is formed as follows ... 

Allosteric activators of PFK include AMP and fructose-2,6-bisphosphate (F2,6BP). Inhibitors include ATP and citrate. The most potent of the allosteric regulator of glycolysis and gluconeogenesis is F2,6BP due to its ability to turn on PFK and turn off the corresponding gluconeogenesis enzyme, fructose-1,6-bisphosphatase, in very low concentrations. 

Activity of glycolysis depends on adenylate energy charge (Figure 13.8) Allosteric Regulation of Phosphofructokinase... 

Note that several of the allosteric regulators are products of other metabolic pathways or are made in other metabolic pathways. These include acetyl-CoA, AMP, F2,6BP, and GIP, (readily converted into G6P). By having regulation dependent on other pathways, glycolysis is coordinately controlled with these pathways as well. 

Basically irrelevant for the Pasteur effect is the allosteric regulation of the pyruvate kinases of yeast and certain animal tissues, which is not intrinsic to glycolysis, but rather is a device for the benefit of the potential switch over to gluconeogenesis. So is the interconversion system of the pyruvate dehydrogenase of animal tissues, which probably is not... 

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