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PubMed1986

Isolation of the structural gene encoding a mutant form of Escherichia coli phosphoenolpyruvate carboxylase deficient in regulation by fructose 1,6-bisphosphate. Identification of an amino acid substitution in the mutant.

The structural gene encoding a mutant Escherichia coli phosphoenolpyruvate carboxylase deficient in regulation by fructose 1,6-bisphosphate (Fru-P2) was isolated from total E. coli PpcI genomic DNA. This mutant gene is located on a 4.4-kilobase SalI DNA fragment which, when ligated to SalI-digested pBR322, resulted in the generation of the plasmid pFS16. Detailed restriction mapping of the wild-type and mutant genes for phosphoenolpyruvate carboxylase revealed the presence of a ClaI restriction site at position 563 of the mutant gene only. This ClaI site is located on a 289 PvuII/DdeI fragment which codes for amino acid residues 174-270 of the phosphoenolpyruvate carboxylase enzyme. When this portion of the mutant gene is present in chimeras of the wild-type and mutant genes, the phosphoenolpyruvate carboxylase produced cannot be activated by Fru-P2. The mutation resulting in the generation of the ClaI site in the mutant gene has also resulted in an amino acid substitution at residue 188; threonine in the wild-type enzyme has been replaced by isoleucine in the mutant enzyme. Comparison of the nucleotide sequence of this 289-base pair PvuII/DdeI region of the mutant gene with its homologous region in the wild-type gene verified that this mutation, which resulted in the generation of the ClaI site, is the only change that has occurred on this 289-base pair fragment of the mutant gene, and thus the amino acid replacement of threonine by isoleucine is the only change that could be linked to the inability of the mutant enzyme to be activated by Fru-P2.

Amino Acid Sequence↗
PubMedDate not supplied

[Mathematical model of stabilization of circadian rhythm in cell energy metabolism].

A mathematical model for circadian self-oscillation in the carbohydrate branch of energy metabolism (CEM) was analysed. The self-oscillations are due to the reciprocal regulation of the activities of 6-phosphofructokinase and fructose-1,6-bisphosphatase by fructose-1,6-bisphosphate. The circadian period was shown to be insensitive to metabolic disturbances because of the presence in CEM of negative feedback mechanisms regulating the activities of the key enzymes 6-phosphofructokinase, fructose-1,6-bisphosphatase, pyruvate kinase and phosphoenolpyruvate carboxykinase. It has been also shown that such mechanisms are largely synergistic in their action.

Adenylate Kinase↗
PubMed1987

Erythrocyte PK deficiency: biochemical characterization of a patient with haemolytic anemia.

Erythrocyte pyruvate kinase deficiency was detected in a Cuban girl with congenital nonspherocytic haemolytic anemia. Kinetic and immunochemical studies showed that the case was different from those hitherto reported. The variant(s) was tentatively designated PK "Alquizar", following the recommendations of the International Committee for Standardization in Hematology.

Adenosine Diphosphate↗
PubMedDate not supplied

[The key role of fructose-2,6-bis-phosphate in the temporal organization of carbohydrate metabolism. An auto-oscillating mathematical model].

A mathematical model describing the periodical temporal organization of the open futile cycle fructose-6-phosphate in equilibrium fructose-1,6-bisphosphate (F6P in equilibrium F1,6P2) is investigated. The oscillations in this cycle are caused by the regulatory cycle F6P in equilibrium fructise-2,6-bisphosphate (F2,6P2), catalyzed by phosphofructokinase-2 (PFK-2) with a cascade of covalent chemical modification. The apparent product activation of PFK-2 by F2,6P2 together with the F2,6P2 outflux from the regulatory cycle create square-shaped oscillations in the concentration of F2,6P2, a powerful reciprocal regulator of the enzymes of the futile cycle F6P in equilibrium F1,6P2. Compared to the mechanisms of the autonomous regulation of the F6P in equilibrium F1,6P2 cycle suggested previously, the new one provides an excellent temporal separation of the glycolytic and gluconeogenic pathways and possesses a considerably larger region of existence of the self-oscillatory behaviour.

Carbohydrate Metabolism↗
PubMed1987

[Effect of fructose-1,6-diphosphate and trental on the erythrocyte aggregating capacity in ischemic heart disease].

It was shown that fructose-1.6-diphosphate was capable of marked suppression of the aggregation power of the blood erythrocytes of patients with acute myocardial infarction and angina of effort. The antiaggregation effect of the drug was dose-related and enhanced with an increase in the time of its contact with erythrocytes. The antiaggregation effect of pentoxifylline was not of distinct dose-related nature. Its antiaggregation power did not considerably depend on the time of incubation with erythrocytes.

Adult↗
PubMed1987

Prevention by fructose-1,6-bisphosphate of cardiac oxidative damage induced in mice by subchronic doxorubicin treatment.

An experimental model of mild, subchronic doxorubicin cardiotoxicity in mice was investigated by monitoring changes of biochemical parameters related to cell response against oxidative stress in both liver and heart. A specific increase of the lactate dehydrogenase isoenzyme typical of the heart was observed for doxorubicin-treated mice. Lipid peroxidation, as evaluated by malondialdehyde determination, and catalase activity were greatly increased in heart and unaffected in liver. On the other hand, these changes can be considered as indicative of early heart damage induced by doxorubicin. Glutathione, glutathione peroxidase, and 6-phosphogluconate dehydrogenase values were not significantly altered by the treatment and glucose-6-phosphate dehydrogenase increased in both liver and heart. Administration of fructose-1,6-bisphosphate strongly reduced the increase of plasma lactate dehydrogenase, heart lipid peroxidation, and heart catalase while no effect on the diagnostically irrelevant increase of glucose-6-phosphate dehydrogenase was observed. The inhibitory effect on the onset of biochemical modification typical of early subchronic doxorubicin cardiotoxicity may be related to stimulation of ATP synthesis by fructose-1,6-bisphosphate and is therapeutically promising in view of the lack of toxicity of fructose-1,6-bisphosphate as a drug.

Animals↗
PubMed1978

Disappearance of oxytocin-induced uterine tiredness by treatment with fructose-1,6-diphosphate. Experimental evidence.

Fructose-1,6-diphosphate (FDP) is able to abolish oxytocin induced spastic inertia in rat uterus. The clinical use of FDP is suggested by observation carried out on 30 deliveries with oxytocin induction. The FDP-treated patients (5 g of FDP in 50 ml of water by intravenous infusion) showed a statistically significant decrease of time elapsed between the beginning of uterine inertia and the recovery of uterine contractions (176 +/- 25.4 min) compared to controls (562 +/- 32.5 min).

Adolescent↗
PubMed1986

Active hepatic glycogen synthesis from gluconeogenic precursors despite high tissue levels of fructose 2,6-bisphosphate.

When fasted rats ate regular lab chow there was a lag time of about 2 h before the concentration of fructose 2,6-bisphosphate (Fru-2,6-P2) in liver began to rise from its low basal level. By contrast, in animals refed on a sucrose-based diet hepatic [Fru-2,6-P2] increased 20-fold (to a value of approximately 12 nmol/g wet weight) during the first hour. These responses correlated with differences in the ability of the two diets to increase the circulating [insulin]/[glucagon] ratio and thus to elevate the ratio of 6-phosphofructo-2-kinase to fructose-2, 6-bisphosphatase. Liver glycogen was deposited briskly in both groups of rats. To assess its mechanism of synthesis (directly from glucose versus indirectly via the gluconeogenic pathway), animals eating the chow or sucrose diets received intravenous infusions of [14C]bicarbonate, [1-14C] fructose, and 3H2O. After isolation, the glycogen was subjected to positional isotopic analysis of its glucose residues. The results established that regardless of the diet the bulk of liver glycogen was gluconeogenic in origin. The fact that with sucrose feeding carbon flow through hepatic fructose-1,6-bisphosphatase remained active despite high levels of Fru-2,6-P2 (a potent inhibitor of this enzyme in vitro) presents a metabolic paradox. Conceivably, the suppressive effect of Fru-2, 6-P2 on hepatic fructose-1,6-bisphosphatase is overridden in vivo by some unknown factor or factors generated in response to sucrose feeding. Alternatively, metabolic zonation in liver might result in the coexistence of hepatocytes rich in Fru-2,6-P2 (high glycolytic, low gluconeogenic, low glycogenic capacitites) with cells depleted of Fru-2,6-P2 (low glycolytic, high gluconeogenic, high glycogenic capacities).

Animals↗
PubMed1986

A comparison between fructose 1,6-diphosphate, glucose, or normal saline infusions and species-specific blood exchange transfusions in the treatment of bowel ischemia.

Infusion of fructose 1,6-diphosphate, (FDP), the rate-limiting substrate in anaerobic metabolism, decreases infarction in the ischemic heart. This study evaluates the effect of FDP (5% in H2O), glucose (D5W), or normal saline (N/S) infusions and species-specific blood (SSB) exchange transfusions on mortality rates and bowel infarction in rats with intestinal ischemia. One hundred twenty Sprague-Dawley male rats (50 to 75 gm) were divided into six experimental groups. Group I controls (n = 20) underwent sham laparotomy. Group II (n = 20) underwent superior mesenteric artery (SMA) occlusion for 90 minutes. Group III rats (n = 20) were infused with FDP with SMA occlusion (90 minutes). Group IV rats (n = 20) were infused with D5W with SMA occlusion (90 minutes). Group V rats (n = 20) were infused with N/S with SMA occlusion (90 minutes). Group VI rats (n = 20) received species-specific exchange transfusion after SMA occlusion (90 minutes). A typical rat given 1 ml of D5W/75 gm had a serum glucose of 478 ng/dl with an osmolality of 293 mosm/L. After being given 1 ml of NS/75 gm, rats had a serum glucose level of 170 mg/dl with an osmolality of 291 mos/ml. Control rats had a serum glucose level of 139 mg/dl with an osmolality of 295 mosm/L. Survival at 48 hours without bowel infarction was 20 of 20 (100%) in group I, three of 20 (15%) in group II, 12 of 20 (60%) in group III, 12 of 20 (60%) in group IV, five of 20 (25%) in group V, and six of 20 (30%) in group VI (p less than 0.05 groups III and IV versus group II). FDP and D5W infusions increased survival after bowel ischemia in the rat. The mechanism of action may involve provision of a substrate for anaerobic metabolism to ischemic bowel via collateral pathways, hemodilution, and/or volume expansion.

Animals↗
PubMed1986

The influence of fructose-1:6-bisphosphate on the release of glycolytic enzymes from cellular structure.

In order to provide information on the relative binding characteristics of glycolytic enzymes, the effect of fructose-1,6-bisphosphate (FBP) on the release of glycolytic enzymes from cultured pig kidney cells treated with digitonin has been studied. In the absence of FBP, a differential release of these enzymes was observed, with the order of retention being aldolase greater than glyceraldehyde-3-phosphate dehydrogenase greater than glucosephosphate isomerase, triosephosphate isomerase, phosphoglycerokinase, phosphoglucomutase, lactate dehydrogenase, enolase, pyruvate kinase and phosphofructokinase. In the presence of fructose-1,6-bisphosphate, the release of aldolase was considerably enhanced, whereas the release of phosphofructokinase and pyruvate kinase was decreased by this metabolite. No significant alterations in the rate of release of the other enzymes was caused by FBP. These data have been discussed in relation to their contribution to the knowledge of the degree of association and order of binding between glycolytic enzymes and the cytoplasmic matrix.

Animals↗
PubMed1979

Regulation of glycogen synthesis and glucose utilization in Escherichia coli during maintenance of the energy charge. Quantitative correlation of changes in the rates of glycogen synthesis and glucose utilization with simultaneous changes in the cellular levels of both glucose 6-phosphate and fructose 1,6-diphosphate.

Treatment of nitrogen-starved cultures of Escherichia coli W4597(K) with sodium azide results in simultaneous changes in both glucose 6-phosphate and fructose 1,6-diphosphate as well as in the rate of glycogen synthesis. Based on these observations, a comprehensive equation was developed which relates the cellular levels of both of these hexose phosphates with the rate of glycogen synthesis. This relationship apparently represents the interaction in vivo between the rate-limiting enzyme of bacterial glycogen synthesis, glucose 1-phosphate adenylyltransferase (adenosine diphosphoglucose synthetase, EC 2.7.7.27), and its substrate glucose 1-phosphate (reflected by glucose 6-phosphate) and its major allosteric activator fructose diphosphate. The form of the equation that describes this relationship was determined from studies presented here of the kinetic properties of the E. coli W4597(K) enzyme in the presence of physiological concentrations of its substrates and modulators. We show here and in subsequent reports of this series that the comprehensive relationship between glycogen synthesis and hexose phosphates can serve as a reference to evaluate the possible participation of new factors in the regulation of glycogen synthesis. Treatment with NaN3 did not change the cellular level of glucose 1-phosphate adenylyltransferase. The value of the adenylate energy charge, (ATP + 1/2 ADP)/(ATP + ADP + AMP), was maintained despite losses of up to 35% in cellular adenylates. The quantitative co-variance between hexose phosphates and the cellular rate of glucose utilization that we previously described for other metabolic conditions was also observed in the azide-treated cultures. We integrate the new information into the system of coordinated regulation of glycogen synthesis, glycolysis, and glucose utilization that we proposed previously.

Adenosine Diphosphate Glucose↗
PubMed1979

The 6-phosphogluconate dehydrogenase reaction in Escherichia coli.

This study is an attempt to relate in vivo use of the 6-phosphogluconate dehydrogenase reaction in Escherichia coli with the characteristics of the enzyme determined in vitro. 1) The enzyme was obtained pure by affinity chromatography and kinetically characterized; as already known, ATP and fructose-1,6-P2 were inhibitors. 2) A series of isogenic strains were made in which in vivo use of thereaction might differ, e.g. a wild type strain versus a mutant lacking 6-phosphogluconate dehydrase, as grown on gluconate; a phosphoglucose isomerase mutant grown on glucose or glycerol. 3) The in vivo rate of use of the 6-phosphogluconate dehydrogenase reaction was determined from measurements of growth rate and yield and from the specific activity of alanine after growth in 1-14C-labeled substrates. 4) The intracellular concentrations of 6-phosphogluconate, NADP+, fructose-1,6-P2, and ATP were measured for the strains in growth on several carbon sources. 5) The metabolite concentrations were used for assay of the enzyme in vitro. The results allow one to calculate how fast the reaction would function in vivo if ATP and fructose-1,6-P2 were its important effectors and if the in vitro assay conditions apply in vivo. The predicted in vivo rates ranged down to as low as one-tenth of the actual rates, and, accordingly, one cannot yet draw firm conclusions about how the reaction is actually controlled in vivo.

Adenosine Triphosphate↗
PubMed1986

Nuclear magnetic resonance studies of carbohydrate metabolism and substrate cycling in Fasciola hepatica.

We have been interested in clarifying unique features of glycolytic metabolism in parasitic trematodes and in developing improved methods for monitoring the effects of pharmacologic agents that may alter functions of the pathway. In the present study metabolism of [1-13C]glucose by the common liver fluke, Fasciola hepatica, was studied both directly with 13C NMR and indirectly by observation of 13C-induced multiplet splitting of the 1H NMR resonances from the glycolytic end-products propionate and acetate. The extent of 13C enrichment of the end-products demonstrated that exogenous glucose was the predominant source of glycolytic substrate under the incubation conditions used. Specific enrichments of propionate and acetate in 13C were similar and enrichments at the acetate C-1 carboxyl and C-2 methyl were identical, demonstrating that acetate is generated preferentially from pyruvate formed by the malic enzyme reaction. End-product synthesized in substrate-free medium following incorporation of a small fraction of [1-13C]glucose into endogenous glycogen demonstrates that glucose equivalents from the most recently synthesized polymeric chains, which have a specific activity in 13C equal to that of the exogenous glucose, are preferentially used for glycogenolysis. Stimulation of flukes with 0.1 mM serotonin results in a reduction of the propionate/acetate 13C enrichment ratio consistent with functional "compartmentation" of glycogen pools having different structures and/or specific enrichment in 13C. Glucose equivalents were incorporated into glycogen in intact flukes with label at both the C-1 and C-6 positions during perfusion with [1-13C]glucose as a consequence of "substrate cycling" at the phosphofructokinase/fructosebisphosphatase enzyme couple. The observed glycogen C-6/C-1 labeling ratio of 0.42 and the net glycolytic flux of 11 mumol/g wet weight/hr imply a total forward flux of about 29 mumol/g wet weight/hr through phosphofructokinase with a reverse flux of about 17 mumol/g wet weight/hr through fructosebisphosphatase. Net glycolytic flux is therefore a poor estimate of the true flux through phosphofructokinase in this preparation.

Acetates↗
PubMed1985

In vivo glycolytic equilibria in dog gracilis muscle.

While the equilibrium assumption and the validity of using total measured concentrations for near equilibrium indicator reactions have been widely tested in liver, these have not been systematically evaluated in skeletal muscle. Vascularly isolated dog gracilis muscles were stimulated via the nerve at 4 Hz, and tissue was sampled by quick freezing at rest and after 10, 15, 30, 60, and 180 s of stimulation or after stimulation in the presence of glycolytic blockade by iodoacetate. Phosphocreatine, creatine, and several glycolytic intermediates were measured in tissue extracts. The in vivo mass action ratios for triosephosphate isomerase and aldolase were evaluated relative to substrate concentrations and compared with equilibrium constants determined in vitro. Although there was evidence of substrate binding at low substrate levels for the triosephosphate isomerase reaction, the in vivo mass action ratios for both reactions stabilized at a constant value at moderate substrate levels and in glycolytically blocked muscles. It was concluded that both enzymes are in apparent equilibrium in vivo, but the equilibrium constants are lower than those determined in vitro. The mass action ratios of the combined creatine kinase, lactate dehydrogenase, glyceraldehyde-phosphate dehydrogenase and phosphoglycerate kinase reactions were determined for resting muscles. These reactions are also at equilibrium and the equilibrium constants are consistent with in vitro values.

Animals↗
PubMed1985

Successful treatment of irreversible hemorrhagic shock in dogs with fructose-1,6 diphosphate and dichloroacetate.

Hemodynamic and metabolic effects of fructose-1,6-diphosphate (F.D.P.) and dichloroacetate sodium (D.C.A.) administration were studied in 17 mongrel dogs during experimentally induced hemorrhagic shock using a modified Wigger's technique. During the oligemic period, which was maintained for 3 hours, a control group of animals (A) received a 5% glucose solution at a rate of 3 mg/kg/min, while the treated group (B) received D.C.A. (175 mg/kg for 30 minutes) and F.D.P. (5 mg/kg/min) as aqueous solutions. After retransfusion of the shed blood, both groups of animals were left to recover. All eight dogs of the control group died within 3 hours following the experiment, while six out of the nine treated dogs survived during a week of follow-up (p = 0.007). Two hours after retransfusion, blood pressure and cardiac index in group B returned to control levels (115 +/- 4.8 mmHg and 0.097 +/- 0.008 liters/min/kg), while group A demonstrated a rapid and progressive deterioration (64 +/- 9.7 mmHg and 0.041 +/- 0.005 liters/min/kg). Severe core hypothermia (down to 33.3 degrees C) developed in group A dogs despite retransfusion, while a normal core temperature was maintained in the treated dogs. Calculated oxygen consumption during the oligemic period was significantly higher in group B animals despite similar calculated oxygen delivery in both groups of animals. Hyperlactemia was significantly lower in group B animals despite F.D.P. administration. This can be attributed to the addition of D.C.A. to the treatment. F.D.P. and D.C.A. administration prevented the occurrence of respiratory failure resulting, most probably, from respiratory muscle fatigue owing to depressed metabolic rate and increased lactate formation in these muscles during the shock period. It is suggested that administration of F.D.P. and D.C.A. during hemorrhagic shock in dogs has a favorable effect on the outcome of this life-threatening condition.

Acetates↗
PubMedDate not supplied

Monovalent cations requirement of the fructose 1,6-bisphosphate-activated pyruvate kinase from E. coli.

The fructose 1,6-bisphosphate-activated pyruvate kinase from Escherichia coli has been purified by a simplified procedure, which gives a homogeneous enzyme in approximately half the working time required by other methods and is suitable for large scale preparations. The activity of the enzyme is strictly dependent on the presence of monovalent cations. Enzyme activity is elicited by K+ and NH4+, but not by Na+. Homotropic cooperativity is displayed in the activation by K+ and NH4+ and heterotropic effects are reciprocally exerted by monovalent cations and other ligands, such as phosphoenolpyruvate and fructose 1,6-bisphosphate. The allosteric nature of such interactions is suggested by changes in heat stability of the enzyme induced by K+ and fructose 1,6-bisphosphate. NH4+, but not K+, at high concentrations, cause an inhibition of enzyme activity.

Cations, Monovalent↗