Gluconeogenesis regulatory enzymes

Fructose-2,6-bisphosphatase, a regulatory enzyme of gluconeogenesis (Chapter 19), catalyzes the hydrolytic release of the phosphate on carbon 2 of fructose 2,6-bisphosphate. Figure 7-8 illustrates the roles of seven active site residues. Catalysis involves a catalytic triad of one Glu and two His residues and a covalent phos-phohistidyl intermediate. 

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. 

D-Fructose 1,6-diphosphatase is a regulatory enzyme playing a key role in the control of gluconeogenesis. A number of mechanisms have been proposed for the regulation of D-fructose 1,6-diphosphatase activity, including allosteric control by AMP,396 inhibition by D-fructose 1,6-bisphosphate, ADP, or ATP, and modification of the sulfhydryl groups of the enzyme.397,398... 

Fl,6BPase is a key regulatory enzyme of gluconeogenesis. It is allosterically inactivated by fructose-... 

Fructose 1,6 bisphosphatase - The primary regulatory enzyme for gluconeogenesis. Inactivated potently by F2,6BP (See Figure 16.17) and AMP. Synthesis of the enzyme is sensitive to hormonal control. 

All of the regulatory enzymes of glycolysis exist as tissue-specific isoenzymes, which alter the regulation of the pathway to match variations in conditions and needs in different tissues. For example, in the liver, an isoenzyme of pyruvate kinase introduces an additional regulatory site in glycolysis that contributes to the inhibition of glycolysis when the reverse pathway, gluconeogenesis, is activated. 

Fructose 1,6-bisphosphatase (FBPase, D-fructose 1,6-bisphosphate 1-phosphohydrolase, EC 3.1.3.11) is a key regulatory enzyme in gluconeo-genesis that catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate (F6P) and inorganic phosphate.235 Five different variants of FBPase have been reported. Since FBPase is a key enzyme in gluconeogenesis, the inhibitors of FBPase are postulated to be useful for the treatment of type-II diabetes. 3s... 

The regulatory enzymes of gluconeogenesis are confined to the liver and kidney. 

Pymvate carboxylase, the first irreversible enzyme in gluconeogenesis, also is a regulatory enzyme. Pymvate can be converted to oxaloacetate (by pymvate carboxylase) or it can be converted to acetyl-CoA (by the pyruvate dehydrogenase complex), which then enters the citric acid cycle. Acetyl-CoA is an allosteric activator of pymvate... 

Succinyl-CoA is converted to succinate by the enzyme succinate thiokinase (succinyl-CoA synthetase). This is the only example in the citric acid cycle of substrate-level phosphorylation. Tissues in which glu-coneogenesis occurs (the hver and kidney) contain two isoenzymes of succinate thiokinase, one specific for GDP and the other for ADP. The GTP formed is used for the decarboxylation of oxaloacetate to phos-phoenolpymvate in gluconeogenesis and provides a regulatory hnk between citric acid cycle activity and the withdrawal of oxaloacetate for gluconeogenesis. Nongluconeogenic tissues have only the isoenzyme that uses ADP. 

The enzyme responsible for this step is fructose 1,6-bisphosphatase. Like its glycolytic counterpart, it is an allosteric enzyme that participates in the regulation of gluconeogenesis. We will return to its regulatory properties later in the chapter. 

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