Citrate fructose-1,6-bisphosphatase

The hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate (Eigure 23.7), like all phosphate ester hydrolyses, is a thermodynamically favorable (exergonic) reaction under standard-state conditions (AG° = —16.7 kj/mol). Under physiological conditions in the liver, the reaction is also exergonic (AG = —8.6 kJ/mol). Fructose-1,6-bisphosphatase is an allosterically regulated enzyme. Citrate stimulates bisphosphatase activity, hut fructose-2,6-bisphosphate is a potent allosteric inhibitor. / MP also inhibits the bisphosphatase the inhibition by / MP is enhanced by fructose-2,6-bisphosphate. 

Fructose 1,6-bisphosphatase is inhibited by AMP but activated by citrate and 3-phosphoglycerate. Thus, in a high-bond-energy state, an increase of citrate and a decrease of AMP combine to activate fructose-1,6-bisphosphatase and to inhibit phosphofructokinase (Fig. 11-10). This promotes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate. 

This exergonic reaction (AG° = -16.7 kJ/mol) is also irreversible under cellular conditions. ATP is not regenerated. Fructose-1,6-bisphosphatase is an allosteric enzyme. Its activity is stimulated by citrate and inhibited by AMP and fructose-2,6-bisphosphate ... 

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. 

Phosphofructokinase (PFK) is a major control point for glycolysis. PFK is allosterically inhibited by ATP and citrate, allosterically activated by AMP, ADP, and F2,6BP. Thus, carbon movement through glycolysis is inhibited at PFK when the cell contains ample stores of ATP and oxidizable substrates. Additionally, PFK is activated by AMP and ADP because they indicate low levels of ATP in the cell. F2,6BP is the major activator, though, because it reciprocally inhibits fructose 1,6 bisphosphatase, which is the gluconeogenic enzyme that catalyzes the reversal of this step. 

The interconversion of fructose 6-phosphate and fructose 1,6-bisphos-phate is stringently controlled (Figure 16.30). As discussed in Section 16.2.1, AMP stimulates phosphofructokinase, whereas ATP and citrate inhibit it. Fructose 1,6-bisphosphatase, on the other hand, is inhibited by AMP and activated by citrate. A high level of AMP indicates that the energy charge is low and signals the need for ATP generation. Conversely,... 

Investigations of liver biopsy material for enzymes involved in lactic acidosis and ketogenesis showed normal activites of pyruvate carboxylase, citrate synthetase, isocitrate dehydrogenase, glutamate-pyruvate transaminase, reduced activity of fructose 1,6-bisphosphatase and notably reduced activity of cytosolic acetoacetyl-CoA thiolase. The latter was found to be due to altered kinetic properties of the enzyme and this was confirmed in cultured skin fibroblasts, the enzyme being much more sensitive to coenzyme A inhibition than the normal enzyme. Activity of succinyl-CoA 3-keto acid-CoA transferase was not reported. 

---