Fructose-1,6-diphosphatase activity

Baker L, Winegrad AI (1970) Fasting hypoglycaemia and metabolic acidosis associated with deficiency of hepatic fructose-1,6-diphosphatase activity. Lancet ii 13 16... 

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... 

Cortisol injections have been reported to increase glucose-6-phosphatase and fructose-1,6-diphosphatase activity. When ethionine is administered in addition to cortisone, phosphatase activity is not increased. This finding suggests that the increase in enzyme activity results from de novo synthesis of an adaptive enzyme in response to an increase of substrate. 

D.C. Kvam and R.E. Parks, Hydrocortisone-induced Changes in Hepatic GlucosC S-Phosphatase and Fructose Diphosphatase Activities, Am. J. Physiol. 198, 21-24... 

Although gluconeogenesis is generally considered to be confined to liver and kidney, evidence for the presence of a specific FDPase in muscle has been reported from a number of laboratories. Significant levels of activity are to be found in skeletal muscle of a wide variety of vertebrates including mammals, birds, and amphibia (71, 72). The levels of activity in white muscle were reported to be similar to those found in liver and kidney, but the enzyme was not detected in heart muscle or in smooth muscle of several species tested. Fructose diphosphatase in crude muscle extracts has been reported to be stimulated by EDTA (72). 

Buchanan, B. B., Schurmann, P. and Kalberer, P. P. (1971) Ferredoxin-activated fructose diphosphatase of spinach chloroplasts. J. Biol. Chem. 246, 5952-5959. 

In order to give useful information about an enzyme, a conformationally restricted active-site-directed analog inhibitor need not bind to the enzyme irreversibly. In a study of the enzyme fructose 1,6-diphosphatase from rabbit liver, Benkovic et al, have investigated the question of the reactive form of the fructose 1,6-diphosphate in the enzymatic process (104,105). Three likely forms are shown in structures 50, 51 and 52. 

Even more efficient bimetallic cooperativity was achieved by the dinuclear complex 36 [53]. It was demonstrated to cleave 2, 3 -cAMP (298 K) and ApA (323 K) with high efficiency at pH 6, which results in 300-500-fold rate increase compared to the mononuclear complex Cu(II)-[9]aneN at pH 7.3. The pH-metric study showed two overlapped deprotonations of the metal-bound water molecules near pH 6. The observed bell-shaped pH-rate profiles indicate that the monohydroxy form is the active species. The proposed mechanism for both 2, 3 -cAMP and ApA hydrolysis consists of a double Lewis-acid activation of the substrates, while the metal-bound hydroxide acts as general base for activating the nucleophilic 2 -OH group in the case of ApA (36a). Based on the 1000-fold higher activity of the dinuclear complex toward 2, 3 -cAMP, the authors suggest nucleophilic catalysis of the Cu(II)-OH unit in 36b. The latter mechanism is comparable to those of protein phosphatase 1 and fructose 1,6-diphosphatase. 

Even more interesting is the observed regioselectivity of 37 its reaction with 2, 3 -cCMP and 2, 3 -cUMP resulted in formation of more than 90% of 2 -phosphate (3 -OH) isomer. The postulated mechanisms for 37 consists of a double Lewis-acid activation, while the metal-bound hydroxide and water act as nucleophilic catalyst and general acid, respectively (see 39). The substrate-ligand interaction probably favors only one of the depicted substrate orientations, which may be responsible for the observed regioselectivity. Complex 38 may operate in a similar way but with single Lewis-acid activation, which would explain the lower bimetallic cooperativity and the lack of regioselectivity. Both proposed mechanisms show similarities to that of the native phospho-monoesterases (37 protein phosphatase 1 and fructose 1,6-diphosphatase, 38 purple acid phosphatase). 

Second, GSH functions, presumably nonenzymically, in the reduction of protein thiols which have become oxidized to mixed disulfides (803). In this latter function GSH in some cases converts inactive enzymes to active ones, or vice versa, and may thus serve as a means of metabolic control. Examples of this important possibility are glycogen synthetase D (EC 2.4.1.11) and fructose-1,6-diphosphatase (EC 3.1.3.11). The D form of glycogen synthetase is dependent for activity upon the presence of glucose 6-phosphate. The enzyme is inactivated by GSSG and reactivated by GSH (204). Mixed disulfide formation between thiols of the enzyme and GSSG leads to a decrease in affinity of the enzyme for its activator (205). 

The specific inhibition of D-fructose 1,6-diphosphatase by AMP decreases if the pH of the solution moves399 to above 9. Inhibition by AMP and catalytic activity can be lost by acetylation of the tyrosine residues with 1-acetylimidazole. The presence of substrate or allosteric effectors protects the tyrosine from acetylation.400 Pyridoxal phosphate can also desensitize the enzyme by forming a Schiff base with L-lysinyl residues401 this indicates some participation of L-lysinyl residues in allosteric regulation.401,402... 

Taketa and coworkers398 reported that ATP and ADP inhibit rabbit-liver D-fructose 1,6-diphosphatase, and that the inhibition results from a conversion of the enzyme into a conformer having low activity. Skeletal-muscle enzyme is inhibited by ADP. 

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