Glycolysis, inhibition

Phosphofructokinase (EC 2.7.1.30) catalyses the phosphorylation of fructose-6-phosphate to fructose-1,6-biphosphate as the key regulatory enzyme of glycolysis. Inhibition of phosphofructokinase by adenosine triphosphate and its activation by adenosine monophosphate and inorganic phosphate is held responsible for the induction of the Pasteur effect (for review see Ramaiah 1974). 

The Pasteur Effect. It is an old observation that cells, e.g. of muscle or yeast, transform much glucose (to lactate or ethanol) imder anaerobic conditions. If oxygen is supplied, however, then not only is anaerobic glycolysis inhibited, but much less glucose actually enters the Embden-Meyerhof pathway. Evidently, the oxidative processes of mitochondria exert some influence back on the cytoplasm. This seems rather sensible physiologically, since in aerobiosis a great quantity of ATP is produced in the respiratory chain and the demands for energy can w ell be met with less substrate. However, this does not explain the mechanism responsible for the effect, which is known as the Pasteur effect. ... 

Glycolysis and the citric acid cycle (to be discussed in Chapter 20) are coupled via phosphofructokinase, because citrate, an intermediate in the citric acid cycle, is an allosteric inhibitor of phosphofructokinase. When the citric acid cycle reaches saturation, glycolysis (which feeds the citric acid cycle under aerobic conditions) slows down. The citric acid cycle directs electrons into the electron transport chain (for the purpose of ATP synthesis in oxidative phosphorylation) and also provides precursor molecules for biosynthetic pathways. Inhibition of glycolysis by citrate ensures that glucose will not be committed to these activities if the citric acid cycle is already saturated. 

Acetyl-CoA is a potent allosteric effector of glycolysis and gluconeogenesis. It allosterically inhibits pyruvate kinase (as noted in Chapter 19) and activates pyruvate carboxylase. Because it also allosterically inhibits pyruvate dehydrogenase (the enzymatic link between glycolysis and the TCA cycle), the cellular fate of pyruvate is strongly dependent on acetyl-CoA levels. A rise in... 

Within glycolysis, the main allosteric control is exercised by phosphofructokinase, a complicated enzyme unusual in that its activity is stimulated by one of its products (ADP) and inhibited by one of its substrates (ATP). One further point about this enzyme which will be important to us later, in Aspergillus spp., elevated levels of ammonium ions relieve phosphofructokinase of inhibition by titrate. 

Let us consider Figure 5.3 again. Both pyruvate kinase and dtrate synthase (enzymes III and V) are inhibited by elevated ATP concentrations. During citric acid production ATP concentrations are likely to arise (ATP produced in glycolysis) and either of these enzymes could, if inhibited, slow down the process. In fact all of the evidence suggests that both enzymes are modified or controlled in some way such that they are insensitive to other cellular metabolites during citric add production. 

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