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[The antiacidotic and cardioprotective effects of fructose-1,6-diphosphate and dehydroascorbic acid].

The antiacidotic and cardioprotective effects of dehydro-L-ascorbic acid and fructose-1,6-diphosphate were compared in experiments of rats. It was found that the both compounds exhibit the antiacidotic effect on the model of metabolic acidosis in the isolated hypoxic heart, decrease the excess-lactate degree, increase ATP level in the myocardium and reduce the size of the necrosis area 4 hours after the modelling of myocardial infarction. The significance of the antiacidotic component in the mechanism of the cardioprotective action of the energy-supplying agents is concluded.

Acidosis↗
PubMed1991

Fructose 2,6-bisphosphate and AMP increase the affinity of the Ascaris suum phosphofructokinase for fructose 6-phosphate in a process separate from the relief of ATP inhibition.

Kinetic data have been collected suggesting that heterotropic activation by fructose 2,6-bisphosphate and AMP is a result not only of the relief of allosteric inhibition by ATP but is also the result of an increase in the affinity of phosphofructokinase for fructose 6-phosphate. Modification of the Ascaris suum phosphofructokinase at the ATP inhibitory site produces a form of the enzyme that no longer has hysteretic time courses or homotropic positive (fructose 6-phosphate) cooperativity or substrate inhibition (ATP) (Rao, G.S. J., Wariso, B.A., Cook, P.F., Hofer, H.W., and Harris, B.G. (1987a) J. Biol. Chem. 262, 14068-14073). This form of phosphofructokinase is Michaelis-Menten in its kinetic behavior but is still activated by fructose 2,6-bisphosphate and AMP and by phosphorylation using the catalytic subunit of cyclic AMP-dependent protein kinase (cAPK). Fructose 2,6-bisphosphate activates by decreasing KF-6-P by about 15-fold and has an activation constant of 92 nM, while AMP decreases KF-6-P about 6-fold and has an activation constant of 93 microM. Double activation experiments suggest that fructose 2,6-bisphosphate and AMP are synergistic in their activation. The desensitized form of the enzyme is phosphorylated by cAPK and has an increased affinity for fructose 6-phosphate in the absence of MgATP. The increased affinity results in a change in the order of addition of reactants from that with MgATP adding first for the nonphosphorylated enzyme to addition of fructose 6-phosphate first for the phosphorylated enzyme. The phosphorylated form of the enzyme is also still activated by fructose 2,6-bisphosphate and AMP.

Adenosine Monophosphate↗
PubMed1991

Yeast phosphofructokinase: studies on thiol reactivity of a cross-linked enzyme form.

Cross-linked yeast phosphofructokinase exhibiting the basic regulatory properties of the unmodified enzyme but no cooperativity with respect to the substrate fructose 6-phosphate was subjected to stopped-flow thiol titration in order to study the influence of allosteric effectors on the level of protein conformation. As found for native phosphofructokinase, the cross-linked enzyme revealed at least two classes of cysteinyl residues which can be distinguished by their reactivity towards 5,5'-dithiobis-(2-nitrobenzoic acid). In spite of the restricted conformational flexibility caused by the intramolecular cross-linking, several fructose phosphates and AMP were capable of diminishing the apparent first-order rate constant (k) of modification of the fast reacting thiol groups by Ellman's reagent. In the presence of ATP, a drastic decrease of the k-value by more than one order of magnitude became apparent. The data are appropriate to support the hypothesis of the existence of multiple conformational determinants in octameric yeast phosphofructokinase and contribute to the understanding of the extremely different stability of the enzyme in the presence of either fructose 6-phosphate or ATP with respect to proteolytic degradation.

Adenosine Triphosphate↗
PubMed1991

Kinetics of 6-phosphofructo-1-kinase from a yeast mutant.

The steady state kinetics of 6-phosphofructo-1-kinase was determined in a cell-free extract obtained from a yeast mutant (DFY 250) and compared with the kinetic properties of the enzyme of a wild-type strain (DFY 1). 6-Phosphofructo-1-kinase from the DFY 250 strain shows a complex kinetic behaviour, which is qualitatively similar to, but quantitatively different from, that of normal yeast 6-phosphofructo-1-kinase. The mutant enzyme has a lower affinity to its activators fructose 6-phosphate, fructose 2,6-bisphosphate and AMP. The inhibiting effect of ATP on the mutant 6-phosphofructo-1-kinase is substantially weaker than on the wild-type enzyme. A complex interaction between fructose 6-phosphate and fructose 2,6-bisphosphate at the 6-phosphofructo-1-kinase from strain DFY 250 is reflected by a remarkable substrate inhibition by fructose 6-phosphate even at saturating fructose 2,6-bisphosphate. The kinetic data were fitted to different variants of the Monod-Wyman-Changeux model by nonlinear regression analysis. It turned out that the influence of fructose 6-phosphate, ATP, AMP and fructose 2,6-bisphosphate on the activity of 6-phosphofructo-1-kinase from wild-type and DFY 250 strain could be described by rate equations of essentially the same structure.

Adenosine Diphosphate↗
PubMed1991

Yeast phosphofructokinase: kinetic characterization of a substrate-imprinted enzyme conformation.

Intramolecular cross-linking of octameric yeast phosphofructokinase was applied to study the effect of substrate-imprinted conformational changes on the regulatory properties of the enzyme:Cross-linking performed in the presence of fructose 6-phosphate yields a substrate-imprinted enzyme species the affinity of which towards this substrate is significantly higher than that of native phosphofructokinase and of the enzyme cross-linked in the absence of fructose 6-phosphate. The enzyme cross-linked in the presence of fructose 6-phosphate does not exhibit cooperativity with respect to this substrate but is still activated by AMP and by fructose 2,6-bisphosphate. This activation consists in an increase of substrate affinity with respect to fructose 6-phosphate. In the absence of positive effectors, the maximum activity of the cross-linked enzyme corresponds to the respective values of native phosphofructokinase when activated by AMP or by fructose 2,6-bisphosphate. At saturating levels of AMP and of fructose 2,6-bisphosphate, nearly identical affinities with respect to fructose 6-phosphate are found, ranging between the Km values of native phosphofructokinase activated by AMP and by fructose 2,6-bisphosphate. Covalent stabilization of the substrate-imprinted enzyme conformation does not affect the interaction of phosphofructokinase with ATP at the substrate-binding site. The results suggest that the allosteric regulation of yeast phosphofructokinase is mainly related to conformational changes controlled by fructose 6-phosphate while the ATP affinity at the catalytic site of the enzyme remains essentially unaffected.

Adenosine Monophosphate↗
PubMed1991

[The characteristics of the cardioprotective action of fructose-1,6-diphosphate].

The cardioprotective effects of fructose-1,6-diphosphate (FDP) were investigated in infarcted rats and in conscious rabbits with myocardial ischemia. The influence of FDP on metabolic acidosis was studied in isolated hypoxic rat hearts. It was shown that FDP did not change the threshold of the initiation of ischemia in conscious rabbits, but decreased necrotic zone in infarcted rat hearts. After administration of FDP the myocardial contractility was prolonged significantly as compared with control under conditions of severe metabolic acidosis. However, FDP was not effective in hypoxic hearts with compensated metabolic acidosis. It was considered, that FDP influenced only ischemic myocytes with the changes in sarcolemmal permeability.

Acidosis↗
PubMed1991

In vivo regulation of monomer-tetramer conversion of pyruvate kinase subtype M2 by glucose is mediated via fructose 1,6-bisphosphate.

The activity of pyruvate kinase, subtype M2 (PKM2), is known to be increased by fructose 1,6-bisphosphate (Fru-1,6-P2), one of the metabolites in the glycolytic pathway. Recently, we have shown that in vitro, Fru-1,6-P2 activated the association of monomer to form the tetrameric PKM2. To ascertain whether this mode of regulation also occurs in vivo, we prepared monomer-specific monoclonal antibody and quantified the monomer formation in situ in cultured cells by immunocytochemistry. The intracellular Fru-1,6-P2 was manipulated by the glucose concentration in the media. At the physiological concentration of glucose (4-6 mM), 30-35% of PK existed as a monomer. However, PKM2 was dissociated into monomer within minutes after cells were deprived of glucose. The maximal level of monomer was detected after 1 h at 37 degrees C. Monomer was rapidly (within minutes) converted to tetramer after addition of glucose. Furthermore, when cells cultured in 10 mM of glucose were treated with cytochalasin B, an inhibitor of the glucose transporter, a maximal level of monomer was detected within 20-30 min. Determination of Fru-1,6-P2 indicated that its intracellular concentration decreased concomitantly with the reduction in glucose concentration in the medium. These results indicate that monomer-tetramer inter-conversion is a major in vivo cellular regulatory mechanism in response to changes in the extracellular glucose concentration via Fru-1,6-P2.

Animals↗
PubMed1990

Comparative study of phosphofructokinase from rat small intestine and liver. Control by fructose-2,6-bisphosphate and other effectors.

As compared to the liver, intestinal mucosa shows a high rate of aerobic glycolysis. This difference has been attributed to the higher activity of the intestinal phosphofructokinase (PFK) isoenzyme. The regulatory properties of rat small intestine and liver PFK were investigated. At pH 8, where PFK activity can be evaluated free of allosteric influences, the specific activity of the liver isoenzyme was 25% higher than that of the intestinal one. At pH 7 the mucosal PFK was activated to 80% of its maximal activity at pH 8, while the liver enzyme showed only a 40% activation. The apparent Kms for Fructose-6-P were 0.47 and 1.03 mM for the mucosal and hepatic isoenzymes, respectively. At 2 mM Fructose-6-P, the optimal ATP concentration for both isoenzymes was 1 mM. Higher ATP concentrations strongly inhibited both enzymes, but, below 3 mM, PFK activity was larger in the mucosal homogenate. In addition, the intestinal PFK was more sensitive to activation by Fructose-2,6-bisphosphate and 6-phosphogluconate, particularly at low Fructose-6-P concentrations, and by AMP below 0.3 mM. These studies suggest that, under physiological conditions, the intestinal isoenzyme is more active than its liver counterpart. This may account for the high rate of aerobic glycolysis observed in the intestinal mucosa.

Animals↗
PubMed1991

[Beneficial effects of fructose-1,6-diphosphate infusion on hepatic regeneration after partial hepatectomy by microwave tissue coagulator].

Experiments were performed to explore the effect of microwave tissue coagulator (MTC) on post-lobectomy regeneration of the liver and the regeneration-promoting effect of fructose-1,6-diphosphate (FDP) on heat injury of the liver after 40% hepatectomy in rats. Concerning the effect of MTC on hepatic regeneration, a MTC group showed a significantly higher serum LDH level on post-operative day 2, compared with a simple ligation group. A significant difference in DNA synthesizing activity between two groups was noted only in the peripheral region of regenerating liver tissue. A marked depression was observed on post-operative day 2 in the MTC group, 433 +/- 50 dpm/micrograms DNA as compared to 782 +/- 111 dpm/micrograms DNA in the simple ligation group, and also in respect of protein synthesis and labeling index. Administration of FDP prior to operation brought about a complete inhibition of the serum LDH elevation. DNA synthesis was significantly enhanced in the peripheral region of regenerating liver tissue in rats pretreated with FDP (422 +/- 52, 783 +/- 112 and 912 +/- 115 dpm/micrograms DNA in the saline, FDP 0.25 mmol/kg and FDP 0.8 mmol/kg groups, respectively). Similar trends were observed as to protein synthesis and labeling index. FDP has been proven to be effective on protection of the liver cells as well as on promotion of the liver regeneration following hepatic resection by MTC.

Animals↗
PubMed1990

Age-related changes in subunit composition and regulation of hepatic 6-phosphofructo-1-kinase.

6-Phosphofructo-1-kinase (PFK) isoenzyme pools from livers of fetal, neonatal, young adult (3 months) and aged (24 months) rats were studied. Near-term liver PFK isoenzyme pools were composed of nearly equal quantities of all three subunits. During the 30 days after birth, the total activity increased by 25%; the amount of the L-type, M-type or C-type subunit was increased 3-fold, was unchanged, or was decreased by 80% respectively. In aged rats, compared with young adults, total PFK activity was unchanged, but the L-type, M-type or C-type subunit decreased by 24%, increased by 39%, or increased by 338% respectively. During neonatal maturation, the changing subunit composition of the hepatic isoenzyme pools led to a decreased susceptibility to ATP inhibition, to a greater apparent affinity for fructose 6-phosphate, and to increased sensitivity to fructose 2,6-bisphosphate. Also, these alterations correlated with the measured increases in fructose 2,6-bisphosphate and the reported optimal rate of hepatic glycolysis/gluconeogenesis.

Aging↗
PubMed1990

A new transient activator of phosphofructokinase during initiation of rapid glycolysis in brain.

The tissue contents of previously known allosteric effectors of brain phosphofructokinase (EC 2.7.1.11) (PFK) and the kinetic behavior of isolated PFK were investigated during the initiation of rapid glycolytic flux in freeze-blown rat brain. Comparing 0- with 5-s brains revealed that there was a 4-fold drop in total tissue content of Fru-6-P and a 5.6-fold increase in Fru-1,6-P2 consistent with activation of PFK. Additionally, analysis of brain content showed a 15-fold increase in AMP, a 3-fold decrease in ATP, a 3-fold decrease in Pi, and a 1.6-fold increase in NH4+. There was no change in Fru-2,6-P2, H+, citrate, or Glc-1,6-P2 or the kinetic profiles of isolated PFK for ATP inhibition or Fru-2,6-P2 activation. We concluded that the observed change in PFK activity could be accounted for only partially by changes in the concentrations of adenine nucleotides and other known effectors. High performance liquid chromatography fractions of extracts obtained from 5-s brains showed the activator with a mobility identical to ribose 1,5-P2 and gave 2 nmol/g (wet weight) at 0 s, 10 nmol/g at 5 s, and 2 nmol/g at 20 s. Assay of PFK in the presence of effectors determined to be in tissue at 5 s showed that addition of 10 nmol/ml ribose 1,5-P2 gave a 4-fold activation of PFK. Based on the rapidity of its formation, its potency of activation, and its similarity in chemical properties to authentic ribose 1,5-P2, we conclude that ribose 1,5-P2 served as the initial activator of PFK in brain.

Adenosine Monophosphate↗
PubMed1978

[Effect of adrenaline, hydrocortisone, insulin and dibutyryl-cAMP on glycolysis and glycogenolysis in white rat liver slices].

Epinephrine, hydrocortisone, and dibutyril cAMP inhibited glycolysis and glucogenolysis. The inhibitory effect was also found when glucose-6-phosphate (G-6-P) was used as a glycolysis substrate, but not for fructose-1,6-diphosphate. This is the evidence of hexokinase activity inhibition by hormones and dibutyril cAMP, and presumably of phospholylase and phosphofructokinase as well. In the simulated cell-free system the hormones produced no effect, dibutyril cAMP inhibiting hexokinase alone. For the realization of hormones effect their interaction with the cell membrane is required. Inhibition of glycogen and G-6-P decomposition to lactic acid in the rat liver slices was not associated with the hormone action on phosphorylase and phosphofructokinase through cAMP and proteinkinase directly. The results obtained indicated the existence of a supplementary mechanism that modified cAMP effect on the activity of the said enzymes. Insulin was effective in any of the cases.

Animals↗
PubMed1990

[Glycolytic activity and fructose 2, 6-bisphosphate changes in rat brain during ischemia].

The brain ischemia of spontaneously hypertensive rat was produced gradually by bilateral ligation of the common carotid arteries. The cortical blood flow was measured with a laser doppler flowmeter before and after ligation of the arteries. At the specified intervals, the brain was frozen in situ with liquid nitrogen. The concentration of blood glucose and glycolytic intermediate in frozen brain were measured and the relationship between glycolytic activity and the concentrations of effectors to PFK-1, such as fructose 2,6-bisphosphate, fructose 1,6-bisphosphate, AMP, ATP, Pi and citrate, was investigated. The changes in glycolytic intermediates, pyridine and adenine nucleotides concentration showed that ischemic change occurred in the brain tissue after 30 min of bilateral ligation of the common carotid arteries, in correlation with the decrease in cortical blood flow. The rate of lactate formation increased during the 30-60 min interval and finally decreased during 60-120 min period of ischemia. This indicates that anaerobic glycolysis was accelerated during the early stages of ischemia. The most potent activator of PFK-1, fructose 2, 6-bisphoshate, increased from 5.3 or 6.7 nmol g during the initial stage of ischemia, and this change preceded the activation of glycolysis and the increase in fructose 1,6-bisphosphate concentration, a result indicated that fructose 2,6-bisphosphate does participate in the activation of glycolysis during brain ischemia in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine Nucleotides↗
PubMed1990

Yeast phosphofructokinase: pre-steady-state and stationary kinetic studies on a cross-linked enzyme form.

A cross-linked form of yeast phosphofructokinase in which up to four of the subunits of the octameric molecule were found covalently linked by dimethyl suberimidate exhibits no cooperativity with respect to fructose 6-phosphate and is only weakly inhibited by ATP. The modified enzyme is activated by AMP and fructose 2,6-bisphosphate. Both effectors abolish ATP inhibition even at low concentration of fructose 6-phosphate and increase the affinity of modified phosphofructokinase to fructose 6-phosphate but are without significant effect on the respective maximum activity. The corresponding kinetic patterns exhibit similarity to those of the native enzyme at high concentration of fructose 6-phosphate. In comparison to native phosphofructo-kinase the extent of activation by AMP and fructose 2,6-bisphosphate is of minor amount. As shown for native phosphofructokinase, the enzyme which had been cross-linked in the absence of any effector shows a lag phase of product formation. This initial transient phase completely disappears if the enzyme is modified in the presence of fructose 6-phosphate, fructose 1,6-bisphosphate, and fructose 2,6-bisphosphate, respectively. The same result is obtained by preincubation of the enzyme cross-linked in the absence of any effector with each of these fructose phosphates. The kinetic properties of the modified enzyme indicate that cooperativity with respect to fructose 6-phosphate is not a prerequisite for the allosteric modulation of enzyme activity by AMP and fructose 2,6-bisphosphate and support the idea of multiple conformational determinants in yeast phosphofructokinase. The results suggest that moderate intramolecular cross-linking can provide a simple experimental tool to stabilize different conformational states of an enzyme.

Adenosine Monophosphate↗
PubMed1990

Modulation of glucose metabolism by sulfonylureas in primary cultures of adult rat hepatocytes.

Addition of tolbutamide (0.1-5 microM) or glipizide (0.05-5 microM) to primary cultures of adult rat hepatocytes caused a dose-dependent increase of fructose 2,6-bisphosphate concentration. This effect was accompanied by a stimulation of the rate of L-lactate production and by an acceleration of the metabolic flux through the reaction catalysed by 6-phosphofructo 1-kinase. Moreover, the continuous presence of tolbutamide during the first 26 hours of culture mimicked long-term insulin effects by raising fructose 2,6-bisphosphate levels and the rate of L-lactate formation. Glucokinase, 6-phosphofructo 1-kinase and total 6-phosphofructo 2-kinase activities were not found to be significantly different in hepatocytes cultured either in the presence or in the absence of sulfonylurea.

Animals↗
PubMed1990

The effects of various anesthetics on tissue levels of fructose-2,6-bisphosphate in rats.

We report that the short-term use of various anesthetic agents prior to decapitation causes alteration of the levels of fructose-2,6-bisphosphate in kidney, brain, heart, muscle, and liver. These data indicate that even light anesthesia can not be used when levels of this metabolite are to be determined. Also, it appears that the use of any of these anesthetics can profoundly alter glucose utilization in many tissues.

Anesthetics↗
PubMed1990

Effect of obstructive jaundice on renal Na-K ATPase activity and ATP contents, their response to E. coli or endotoxin and effect of 1-6 fructose diphosphate.

A two-week bile duct ligation (BDL) in Sprague-Dawley (SD) rats raised the serum billirubin level and decreased the mean arterial blood pressure and renal cortical ATP contents compared with those in sham-operated (SO) rats (3.6 +/- 1.15 mg% vs 0.54 +/- 0.36, P less than 0.001; 69 +/- 24 mmHg vs 86 +/- 21, P less than 0.05; 3.72 +/- 0.86 x 10(-10) mol/mg tissue vs 7.27 +/- 0.18, P less than 0.05). No difference could be found in the medullary ATP contents (8.42 +/- 2.20 vs 8.70 +/- 2.80, P = NS). In SO rats, injection of endotoxin (0.7 mg/kg BW) and E. coli (3.1 x 10(5) bacteria/100 g BW) reduced cortical ATP content to 1.86 +/- 0.97 and 1.30 +/- 0.47 (P less than 0.001), and medullar ATP to 1.33 +/- 0.31 and 2.12 +/- 0.46 (P less than 0.001) respectively. In BDL rats, the same treatment led to further decrease in cortical ATP to 1.25 +/- 0.40 and 0.62 +/- 0.20, medullary ATP to 0.97 +/- 0.41 and 1.64 +/- 0.83 (P less than 0.001). Basal Na-K ATPase activity in BDL is the same compared with that in SO both in the cortex (2.85 +/- 2.2 mumol/mgpr/h vs 2.19 +/- 0.75; P = NS) and medulla (2.79 +/- 1.83 vs 3.05 +/- 1.38; P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗