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PubMed1990

Oxygen radical injury and loss of high-energy compounds in anoxic and reperfused rat heart: prevention by exogenous fructose-1,6-bisphosphate.

Isolated Langendorff-perfused rat hearts after 10 minutes preperfusion, were subjected to a substrate-free anoxic perfusion (20 minutes) followed by 20 minutes reperfusion with a glucose-containing oxygen-balanced medium. Under the same perfusion conditions, the effect of exogenous 5mM fructose-1,6-bisphosphate has been investigated. The xanthine dehydrogenase to xanthine oxidase ratio, concentrations of high-energy phosphates and of TBA-reactive material (TBARS) were determined at the end of each perfusion period in both control and fructose-1,6-bisphosphate-treated hearts. Results indicate that anoxia induces the irreversible transformation of xanthine dehydrogenase into oxidase as a consequence of the sharp decrease of the myocardial energy metabolism. This finding is supported by the protective effect exerted by exogenous fructose-1,6-bisphosphate which is able to maintain the correct xanthine dehydrogenase/oxidase ratio by preventing the depletion of phosphorylated compounds during anoxia. Moreover, in control hearts, the release of lactate dehydrogenase during reperfusion, is paralleled by a 50% increase in the concentration of tissue TBARS. On the contrary, in fructose-1,6-bisphosphate-treated hearts this concentration does not significantly change after reoxygenation, while a slight but significant increase of lactate dehydrogenase activity in the perfusates is observed. On the whole these data indicate a direct contribution of oxygen-derived free radicals to the worsening of post-anoxic hearts. A hypothesis on the mechanism of action of fructose-1,6-bisphosphate in anoxic and reperfused rat heart and its possible application in the clinical therapy of myocardial infarction are presented.

Animals↗
PubMed1992

Ischemia and reperfusion: effect of fructose-1,6-bisphosphate.

Several lines of evidence indicating a close relationship among ischemia, concentration of high-energy metabolites and onset of the "oxygen paradox" in reperfused tissues have been published. In this framework, we have recently studied the effects of exogenous fructose-1,6-bisphosphate on energy metabolism and on oxygen free radical damages of isolated rat heart subjected to anoxia and reoxygenation. In comparison with control groups, hearts perfused in the presence of 5 mM fructose-1,6-bisphosphate throughout the different perfusion conditions showed higher concentrations of energy metabolites at the end of anoxia, most of which were normalized after reperfusion. Furthermore, in comparison with control hearts, a reduction of tissue malondialdehyde and of lactate dehydrogenase release in the perfusate was observed in fructose-1,6-bisphosphate-perfused hearts. In this article we review most of the available data concerning the ability of fructose-1,6-bisphosphate to protect from ischemia and reperfusion damage outlining those recent findings which contributed both to clarify the pharmacological profile of the drug and to give an insight in its probable mechanism of action.

Animals↗
PubMed1990

ATP inhibition of Phycomyces pyruvate kinase: a kinetic study of the inhibitory effects on the allosteric kinetics shown by the enzyme.

Studies on ATP effects on the allosteric kinetics shown by pyruvate kinase from Phycomyces blakesleeanus NRRL 1555 (-) are reported. Phosphoenolpyruvate showed an allosteric ATP-dependent substrate inhibition. The results supported the existence of spatially distinct catalytic binding sites and the inhibitory binding sites for phosphoenolpyruvate, and ATP showed opposite heterotropic effects with respect to these two types of binding site. With respect to Mg2+ ions, ATP caused a negative heterotropic effect. The global inhibitory effect of ATP was in agreement with the predictions postulated by the two-state concerted-symmetry model of Monod, Wyman and Changeux.

Adenosine Triphosphate↗
PubMed1991

Characterization of the fructose 1,6-bisphosphate-activated, L(+)-lactate dehydrogenase from Thermoanaerobacter ethanolicus.

The L(+)-lactate dehydrogenase from Thermoanaerobacter ethanolicus wt was purified to a final specific activity of 598 mumol pyruvate reduced per min per mg of protein. The specific activity of the pure enzyme with L(+)-lactate was 0.79 units per mg of protein. The M(r) of the native enzyme was 134,000 containing a single subunit type of M(r) 33,500 indicating an apparent tetrameric structure. The L(+)-lactate dehydrogenase was activated by fructose 1,6-bisphosphate in a cooperative manner affecting Vmax and Km values. The activity of the enzyme was also effected by pH, pyruvate and NADH. The Km for NADH at pH 6.0 was 0.05 mM and the Vmax for pyruvate reduction at pH 6.0 was 1082 units per mg in the presence of 1 mM fructose 1,6-bisphosphate. The enzyme was inhibited by NADPH, displaying an uncompetitive pattern. This pattern indicated that NADPH was a negative modifier of the enzyme. The role of L(+)-lactate dehydrogenase in controlling the end products of fermentation is discussed.

Bacteria, Anaerobic↗
PubMed1979

Neutral lipid accumulation in yeast due to inositol deficiency: kinetic studies on the reciprocal regulation by fructose bisphosphate and citrate of yeast acetyl CoA carboxylase.

Neutral lipids, especially triacylglycerols, accumulated due to myo-inositol deficiency both in the cells of Saccharomyces carlsbergensis (Hayashi et al. (1976) J. Biol. Chem., 251, 5759--5769) and in the liver of the rat (Hayashi et al. (1974) Biochim. Biophys. Acta, 360, 134--155). The accumulation of triacylglycerols in the deficient yeast resulted, at least partly, from an enhancement of acetyl CoA carboxylase activity. The activation of the enzyme reflected the fluctuation due to the deficiency in the levels of fructose bisphosphate and citrate (Hayashi et al. (1978) Biochim. Biophys. Acta, 540, 231--237). Thus, the kinetics of the regulation of acetyl CoA carboxylase by these intermediates was studied. In physiological concentrations fructose bisphosphate sigmoidally activated acetyl CoA carboxylase from yeast with the Hill coefficient of 3, while citrate counteracted the fructose bisphosphate activation in a sigmoidal manner with the Hill coefficient of 2. Fructose bisphosphate markedly increased the apparent Vmax value of acetyl CoA carboxylase for the substrate, ATP and slightly decreased the apparent Km value. Citrate greatly decreased the apparent Vmax value increased by fructose bisphosphate.

Acetyl-CoA Carboxylase↗
PubMed1991

Malonyl-CoA in skeletal muscle and liver of streptozotocin-diabetic rats.

Malonyl-CoA, the inhibitor of carnitine palmitoyl transferase I, has been examined in this study in the muscle and liver of diabetic rats. Male Sprague-Dawley rats were rendered diabetic with streptozotocin (6 mg/100 g body wt). The gastrocnemius/plantaris muscles and liver samples were frozen at liquid nitrogen temperature. Muscle malonyl-CoA was 1.8 +/- 0.2 pmol/mg in control rats and 1.5 +/- 0.2 pmol/mg in the diabetic rats. This difference was not statistically significant. Liver malonyl-CoA of control rats was 8.6 +/- 0.8 pmol/mg, in comparison to 4.3 +/- 0.6 pmol/mg in diabetic rats. In the liver, high concentrations of malonyl-CoA inhibit fatty acid oxidation and ketogenesis. Failure of malonyl-CoA to decline in muscle in the diabetic may be responsible in part for the diversion of fatty acids to the liver, thereby enhancing hepatic fatty acid oxidation and ketogenesis.

3-Hydroxybutyric Acid↗
PubMed2003

Effects of n-3 fatty acid, fructose-1,6-diphosphate and glutamine on mucosal cell proliferation and apoptosis of small bowel graft after transplantation in rats.

AIM: To evaluate the effects of n-3 fatty acids (n-3FA), fructose-1,6-diphosphate (FDP) and glutamine (GLN) on mucosal cell proliferation and apoptosis of small bowel graft. METHODS: One hundred and ninety-six inbred strain Wistar rats were grouped as donors and recipients, and underwent heterotopic small bowel transplantation (SBT). n-3FA, FDP and GLN were administered via gastric tube as well as venous infusion for 10 days before and after surgery, respectively. The proliferation and apoptosis of mucosal cells were analyzed with flow cytometry and in situ cell death detection kits. RESULTS: Apparent apoptosis and minor proliferation of mucosal cells of small bowel graft after transplantation were observed. A higher mucosal cell proliferative index and lower apoptotic index were found in all small bowel grafts after supplying with n-3FA, FDP and GLN. CONCLUSION: Nutritional support with n-3FA, FDP and GLN promotes mucosal cell proliferation significantly, and prevents mucosal cell from undergoing apoptosis with different degrees. These regulatory effects on the apoptosis alter the structure and absorption function of transplanted small bowel favorably.

Animals↗
PubMed1998

The phosphatase inhibitors, orthovanadate and levamisole, inhibit induction of erythroid differentiation and abrogate the associated inhibition of glycolysis.

Alterations in protein tyrosine phosphate (PTP), lactate, and fructose 2,6-bisphosphate (F-2,6-P2) levels have been associated with induced MEL cell differentiation and commitment to terminal cell division (TCD). The possible relationships of perturbations in PTP metabolism and reduction in lactate formation during differentiation were investigated utilizing sodium orthovanadate, Na3VO4, primarily an inhibitor of PTP phosphatases, and levamisole, considered an alkaline phosphatase inhibitor. Both of these compounds were found to effectively inhibit the TCD-associated differentiation induced by DMSO, HMBA, and Na butyrate and to abrogate the differentiation-associated reduction in lactate accumulation due to these agents. However, they were found not to inhibit hemin-induced hemoglobin synthesis which is independent of TCD and does not alter lactate metabolism. Two brominated levamisole analogs, L-p-bromotetramisole and D-p-bromotetramisole, were also found to be inhibitors of TCD-associated differentiation and to be effective at even lower concentrations than levamisole. The changes in TCD-associated differentiation and lactate production exhibited the same concentration-dependence with respect to the inhibitors. These findings strengthened the theory that TCD-associated differentiation, decreased lactate production, and sensitivity to phosphatase inhibitors are all associated. Since the induction of MEL cell differentiation has been shown to be associated with, and is thought to be due to, the induction of PTP phosphatase activity and Na3VO4 is thought to inhibit the differentiation by inhibiting PTP phosphatase activity, the effect of levamisole on PTP levels was determined. Levamisole, like Na3VO4, was found to increase the tyrosine phosphate levels of proteins of similar molecular weights in intact cells in both the presence and absence of a differentiation inducer. Several phosphotyrosine-containing, similarly sized proteins were particularly affected by differentiation induction and by Na3VO4 and levamisole treatment. Changes in the levels of tyrosine phosphate-containing proteins of approximately 92-96, 60, and 38 kd were particularly noticeable. The induction of differentiation reduced PTP levels and inhibition of differentiation due to treatment with either Na3VO4 or levamisole increased their levels. These data suggest relationships between signal transduction pathways involved in differentiation and TCD, the regulation of lactate and F-2,6-P2 metabolism, and PTP levels.

Animals↗
PubMedDate not supplied

Physiological effects of intravenous fructose 1.6-diphosphate on diaphragmatic function in malnourished patients with COPD.

BACKGROUND: A low body mass index is one of the strongest predictors of mortality in Chronic Obstructive Pulmonary Disease (COPD) patients. Under-nutrition is often associated with skeletal muscle wasting and hypophosphatemia. AIM AND METHODS: In a pilot, randomised, double-blind placebo-controlled study, we assessed the physiological effects of phosphorous administration in 17 stable undernourished COPD patients, on diaphragmatic function, breathing pattern, neuromuscular drive (P0.1) and dyspnea score. Fructose 1.6-diphosphate (FDP) or placebo was administered i.v. for 7 consecutive days. RESULTS: FDP administration was associated with a marked increase in inspiratory time (Ti) that induced a significant rise (p < 0.05) in the Pressure Time Product of the diaphragm per breath (PTPdi/b). However, since breathing frequency also decreased, the Pressure Time Product per minute of the diaphragm (PTPdi/min), index of diaphragmatic energy expenditure was markedly reduced. The efficiency of the respiratory pump in clearing CO2 was also improved, although not significantly, in the FDP group (p = 0.09) as well as the maximal transdiaphragmatic pressure during the sniff manoeuvre (Pdi,sniff). CONCLUSIONS: This pilot physiological study showed that phosphorus replacement in undernourished, stable COPD patients, may be associated with a complex modification in respiratory pattern and diaphragmatic functions, leading to a marked although not significant reduction in PTPdi/min.

Aged↗
PubMed1999

Kinetic properties and tissular distribution of mammalian phosphomannomutase isozymes.

Human tissues contain two types of phosphomannomutase, PMM1 and PMM2. Mutations in the PMM2 gene are responsible for the most common form of carbohydrate-deficient glycoprotein syndrome [Matthijs, Schollen, Pardon, Veiga-da-Cunha, Jaeken, Cassiman and Van Schaftingen (1997) Nat. Genet. 19, 88-92]. The protein encoded by this gene has now been produced in Escherichia coli and purified to homogeneity, and its properties have been compared with those of recombinant human PMM1. PMM2 converts mannose 1-phosphate into mannose 6-phosphate about 20 times more rapidly than glucose 1-phosphate to glucose 6-phosphate, whereas PMM1 displays identical Vmax values with both substrates. The Ka values for both mannose 1,6-bisphosphate and glucose 1,6-bisphosphate are significantly lower in the case of PMM2 than in the case of PMM1. Like PMM1, PMM2 forms a phosphoenzyme with the chemical characteristics of an acyl-phosphate. PMM1 and PMM2 hydrolyse different hexose bisphosphates (glucose 1,6-bisphosphate, mannose 1,6-bisphosphate, fructose 1,6-bisphosphate) at maximal rates of approximately 3.5 and 0.3% of their PMM activity, respectively. Fructose 1,6-bisphosphate does not activate PMM2 but causes a time-dependent stimulation of PMM1 due to the progressive formation of mannose 1,6-bisphosphate from fructose 1,6-bisphosphate and mannose 1-phosphate. Experiments with specific antibodies, kinetic studies and Northern blots indicated that PMM2 is the only detectable isozyme in most rat tissues except brain and lung, where PMM1 accounts for about 66 and 13% of the total activities, respectively.

Animals↗
PubMed1999

Alteration of substrate specificity by a naturally-occurring aldolase B mutation (Ala337-->Val) in fructose intolerance.

A molecular analysis of human aldolase B genes in two newborn infants and a 4-year-old child with hereditary fructose intolerance, the offspring of a consanguineous union, has identified the novel mutation Ala337-->Val in homozygous form. This mutation was also detected independently in two other affected individuals who were compound heterozygotes for the prevalent aldolase B allele, Ala149-->Pro, indicating that the mutation causes aldolase B deficiency. To test for the effect of the mutation, catalytically active wild-type human aldolase B and the Val337 variant enzyme were expressed in Escherichia coli. The specific activities of the wild-type recombinant enzyme were 4.8 units/mg and 4.5 units/mg towards fructose 1,6-bisphosphate (FBP) and fructose 1-phosphate (F-1-P) as substrates with Michaelis constants of 4 microM and 2.4 mM respectively. The specific activities of purified tetrameric Val337 aldolase B, which affects an invariant residue in the C-terminal region, were 4.2 units/mg and 2.6 units/mg towards FBP and F-1-P as substrates respectively; the corresponding Michaelis constants were 22 microM and 24 mM. The FBP-to-F-1-P substrate activity ratios were 0.98 and 1.63 for wild-type and Val337 variant enzymes respectively. The Val337 mutant aldolase had an increased susceptibility to proteolytic cleavage in E. coli and rapidly lost activity on storage. Comparative CD determinations showed that the Val337 protein had a distinct thermal denaturation profile with markedly decreased enthalpy, indicating that the mutant protein is partly unfolded. The undegraded mutant had preferentially decreased affinity and activity towards its specific F-1-P substrate and maintained appreciable activity towards FBP. In contrast, fluorescence studies of the mutant showed an increased binding affinity for products of the aldolase reaction, indicating a role for the C-terminus in mediating product release. These findings in a rare but widespread naturally occurring mutant implicate the C-terminus in the activity of human aldolase B towards its specific substrates and demonstrate its role in maintaining the overall stability of the enzyme tetramer.

Amino Acid Substitution↗
PubMedDate not supplied

[Changes in the level of fructose-2,6-biphosphate in peripheral blood lymphocytes in patients with diabetes mellitus].

Variation of fructose 2,6-bisphosphate (F-2,6-P2) content in the peripheral blood lymphocytes of patients with diabetes mellitus (type II) was investigated. The 2.5-fold increase of F-2,6-P2 level compared with to the control group was observed in untreated patients with early stage of the disease. In patients using of peroral antidiabetic drugs that corrected diabetes F-2,6-P2 level was approached to the normal one. At the same time F-2,6-P2 content decreases in patients with severe (noncorrected) diabetes mellitus. The possible mechanisms of regulation of lymphocyte F-2,6-P2 concentration in normal conditions and diabetes mellitus are discussed.

Adult↗
PubMed1998

[Clinical study of fructose 1,6-diphosphate on myocardial ischemia/reperfusion injuries].

Twenty ventricular septal defect patients who underwent cardiopulmonary bypass (CPB) were divided into 1,6-diphosphate group and controlled group (10 cases each). Blood samples were taken at pre- and post-cardiopulmonary bypass 30 min, 6 h, and 24 h to determine lactate dehydrogenase enzyme(LDH), creatine kinase enzyme(CK) and its isoenzyme(CK-MB) levels. We found that 1,6-diphosphate decreased the increasing levels of LDH, CK, and CK-MB after cardiopulmonary bypass. It is suggested that 1,6-diphosphate may attenuate myocardial ischemia/reperfusion injuries during cardiopulmonary bypass.

Cardioplegic Solutions↗
PubMed1979

Glycogen synthase Hymenolepis diminuta. I. Allosteric activation and inhibition.

Glycogen synthase (UDP glucose: glycogen alpha-4-glycosyltransferase, EC2.4.1.11) of the tapeworm Hymenolepis diminuta exists in 2 forms: 1) the I-form (independent), which has significant activity in the absence of glucose 6-phosphate (G6P); and 2) the phosphorylated D-form (dependent), which has no enzymatic activity unless G6P is present. The activity of the I-form is greatly enhanced by a variety of allosteric effectors which have, as their common feature, 1 or more phosphate groups. These include inorganic phosphate (Pi), several sugar phosphates, some phosphorylated glycolytic intermediates, and nucleoside mono- and triphosphates. Competition studies suggest that while most of the positive effectors act at the same site on the enzyme (the "G6P site"), fructose 1,6-diphosphate (FDP) and 2,3-diphosphoglyceric acid (2,3DPG) act at low concentrations to stimulate the enzyme at another locus (the "diphosphate site"), while at high concentrations they competitively inhibit the binding of G6P and of the other activators. The inhibition by high uridine monophosphate (UMP) concentrations is competitive only with the activator uridine triphosphate (UTP), suggesting the existence of a third type of allosteric site (the "uridine nucleotide site"). This third site may be the locus for feedback inhibition by the product uridine diphosphate (UDP), a control mechanism which has been observed to occur in mammalian systems. The allosteric control of the D-form of the enzyme is comparatively simple, apparently involving only one site (the "G6P site") that binds a few effects with greatly reduced affinity. Pi reverses the activation of the D-form by G6P.

Allosteric Regulation↗
PubMed2000

[Effect of fructose-1,6-diphosphate on myocardial purin and pyrimidin metabolism during coronary artery bypass grafting surgery].

During ischaemia, the glycolytic pathway (Embden-Meyerhof) is up regulated in an attempt to produce ATP anaerobically. However, this is short-lived due to negative feedback on the key glycolytic enzyme phosphofructokinase by accumulating lactate. Fructose-1,6-diphosphate (FDP), a high energy intermediary metabolite of this pathway, is unique in that is enters glycolysis distal to this inhibitory site. Exogenously administered FDP should therefore theoretically yield ATP independent of lactate accumulation and thereby ameliorate ischaemic injury. Clinical benefit has been shown in coronary artery bypass grafting (CABG) surgery, congestive cardiac failure and adult respiratory distress syndrome. Ischaemia-reperfusion injury induced by cardiopulmonary bypass (CPB) presents clinically as an impairment of myocardial function in the postoperative period. At a cellular level this reflects myocardial metabolic changes and nucleotide degradation (directly linked to high energy phosphate turnover). Quantification of myocardial nucleotide catabolite release therefore provides useful information regarding intermediary metabolism and cytoprotection conferred to myocardial (inosine, uridine) and endothelial (hypoxanthine) tissue. The authors investigated the myocardial cytoprotective effects of FDP in 16 patients scheduled for elective CABG surgery. Aortic and coronary sinus blood were collected directly into liquid nitrogen and analysed by high performance liquid chromatography prior to CPB and at different time points after reperfusion. FDP was administered intravenously in 8 patients and 5% dextrose was administered in 8 other patients. Analysis of transmyocardial (coronary sinus-aortic) nucleotide metabolite levels showed increased release of inosine, hypoxanthine and uridine in both the FDP and the control groups following reperfusion. However, compared to baseline (pre-aortic clamping) values, hypoxanthine and inosine concentrations were significantly elevated at 0, 1, 5 and 10 minutes following reperfusion in the control group. This was in contrast to earlier recovery to baseline levels (after 5 minutes of reperfusion) in the FDP group. Furthermore, when compared to control group, the hypoxanthine and inosine concentrations were significantly decreased by FDP treatment. Uridine concentrations were significantly elevated at 1 and 5 minutes in the control group and no significant change was observed in the FDP group. In conclusion, these data suggest that FDP, through an intermediary metabolic effect, may contribute to myocardial and endothelial cytoprotection during the ischaemic insult of cardiac surgery.

Adult↗
PubMed2000

Dietary P(i) deprivation in rats affects liver cAMP, glycogen, key steps of gluconeogenesis and glucose production.

We previously reported [Xie, Li, Méchin and van de Werve (1999) Biochem. J. 343, 393-396] that dietary phosphate deprivation for 2 days up-regulated both the catalytic subunit and the putative glucose-6-phosphate translocase of the rat liver microsomal glucose-6-phosphatase system, suggesting that increased hepatic glucose production might be responsible for the frequent clinical association of hypophosphataemia and glucose intolerance. We now show that liver cAMP was increased in rats fed with a diet deficient in P(i) compared with rats fed with a control diet. Accordingly, in the P(i)-deficient group pyruvate kinase was inactivated, the concentration of phosphoenolpyruvate was increased and fructose 2, 6-bisphosphate concentration was decreased. Phosphoenolpyruvate carboxykinase activity was marginally increased and glucokinase activity was unchanged by P(i) deprivation. The liver glycogen concentration decreased in the P(i)-deficient group. In the fed state, plasma glucose concentration was increased and plasma P(i) and insulin concentrations were substantially decreased in the P(i)-deficient group. All of these changes, except decreased plasma P(i), were cancelled in the overnight fasted P(i)-deficient group. In the fasted P(i)-deficient group, immediately after a glucose bolus, the plasma glucose level was elevated and the inhibition of endogenous glucose production was decreased. However, this mild glucose intolerance was not sufficient to affect the rate of fall of the glucose level after the glucose bolus. Taken together, these changes are compatible with a stimulation of liver gluconeogenesis and glycogenolysis by the P(i)-deficient diet and further indicate that the liver might contribute to impaired glucose homeostasis in P(i)-deficient states.

Animals↗