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PubMed1997

Use of 3-D computer modelling and kinetic studies to analyse grapefruit pyrophosphate-dependent phosphofructokinase.

The glycolytic reaction of grapefruit PPi-dependent phosphofructokinase (PFP) depends on the presence of Fru-2,6-P2 (Ka = 6.7 nM). This molecule was further demonstrated in grapefruit juice sac cells. Citrate, alpha-ketoglutarate and isocitrate competitively inhibited the binding of Fru-2,6-P2 to PFP. The affinity for Fru-6-P (Km = 159 microM) and PPi (Km = 33 microM) were not affected by the addition of these molecules. In the gluconeogenic reaction, the presence of Fru-2,6-P2 did not affect the Km of Fru-1,6-P2 (61 microM) in contrast to orange fruit PFP. These results led to the building of a computer model of PFP, based on the known structure of Bacillus stearothermophilus ATP-dependent phosphofructokinase (ATP-PFK). The results show that catalysis of Fru-6-P in the alpha chain is most unlikely, due to amino-acid substitutions and that Fru-2,6-P2 can bind between the alpha and beta subunits.

Adenosine Diphosphate↗
PubMed2003

Fructose-1,6-biphosphate prevents excitotoxic neuronal cell death in the neonatal mouse brain.

The excitotoxic cascade may represent an important pathway leading to brain damage and cerebral palsy. Brain lesions induced in newborn mice by ibotenate (acting on N-methyl-D-aspartate receptors) and by S-bromowillardiine (acting on alpha-3-amino-hydroxy-5-methyl-4-isoxazole propionic acid and kainate receptors) mimic some aspects of white matter cysts and transcortical necrosis observed in human perinatal brain damage. Fructose 1,6-biphosphate (FBP) is a high-energy glycolytic pathway intermediate which, in therapeutic doses, is non-toxic and neuroprotective in hypoxic-ischemic models of brain injury. Mechanisms of action include modulation of intracellular calcium through phospholipase C (PLC) activation. The goal of this study was to determine the neuroprotective effects of FBP in a mouse model of neonatal excitotoxic brain injury. Mice that received intraperitoneal FBP had a significant reduction in size of ibotenate-induced (80% reduction) or S-bromowillardiine-induced (40% reduction) cortical plate lesions when compared with control animals. Studies of fragmented DNA and cleaved caspase 3 confirmed the survival promoting effects of FBP. FBP had no detectable effect on excitotoxic white matter lesions. The effects of FBP were antagonized by co-administration of PLC, protein kinase C or mitogen-associated protein kinase inhibitors but not by protein kinase A inhibitor. A moderate, transient cooling of pups immediately after the insult extended the therapeutic window for FBP, as FBP administered 24 h after ibotenate was still significantly neuroprotective in these pups. This data extends the neuroprotective profile of FBP in neonatal brain injury and identifies gray matter lesions involving N-methyl-D-aspartate receptors as a major target for this promising drug.

Alanine↗
PubMed2001

Rapeseed chloroplast thioredoxin-m. Modulation of the affinity for target proteins.

The stroma of higher plant chloroplasts contains two thioredoxins (Trx) with different specificity for the reduction of protein disulfide bonds. Based upon electrostatic features of domains that participate in the thiol/disulfide exchange, we prepared mutants of rapeseed Trx-m bearing opposite charges at a single position and subsequently analyzed their action on the activation of rapeseed chloroplast fructose 1,6-phosphate (CFBPase). The replacement of Pro-35 with lysine and glutamic residues enhanced and impaired, respectively, the stimulation of CFBPase relative to the wild-type and the P35A mutant. Furthermore, the shielding of electrostatic interactions with high concentrations of KCl greatly increased and concurrently made indistinguishable the affinity of all variants for CFBPase. The capacity to stimulate the enzyme activity likewise was enhanced concertedly by fructose-1,6-bisphosphate and Ca(2+) but, at variance with the action of KCl, remained sensitive to charges in the side chain of mutants. These results were consistent with a mechanism in which intermolecular electrostatic interactions and intramolecular non-covalent interactions control the formation of the non-covalent complex between reduced Trx and oxidized CFBPase and, in so doing, modulate the thiol/disulfide exchange.

Amino Acid Substitution↗
PubMed1998

Interaction of M1 and M2 isozymes pyruvate kinase from human tissues with phospholipids.

The effect of pH and the presence of FBP on the interaction of skeletal muscle (PK-M1) and kidney or tumor meningioma (PK-M2) pyruvate kinase with the phospholipids liposomes were investigated by ultracentrifugation and steady-state kinetics and were compared with those results obtained using the bovine heart (PK-M1) isoenzyme which we previously studied. Pyruvate kinase specific activity increases upon the interaction with liposomes. The activation is specifically sensitive to presence of phosphatidylserine (PS) in liposomes. Liposomes made of phosphatidylcholine + phosphatidylserine mixture are good adsorptive systems for both human and bovine of M-type isozymes at low ionic strength. Interaction of PK-M1 with PS liposomes results in the change of Vmax and K(m) values for PEP without marked effect on Hill coefficients. Addition of PS liposomes to PK-M2 induces hyperbolic saturation curves for PEP.

Adsorption↗
PubMed1998

A fluorescence study of ligand-induced conformational changes in cytosolic fructose-1,6-bisphosphatase from germinating castor oil seeds.

The intrinsic fluorescence of homogeneous castor oil seed cytosolic fructose-1,6-bisphosphatase (FBPasec) was used as an indicator of conformational changes due to ligand binding. Binding of the substrate and the inhibitor fructose-2,6-bisphosphate (F-2,6-P2) was quantitatively compared to their respective kinetic effects on enzymatic activity. There are two distinct types of substrate interaction with FBPasec, corresponding to catalytic and inhibitory binding, respectively. Inhibitory substrate binding shares several characteristics with F-2,6-P2 binding which indicates that both ligands bind at the same site. However, F-2,6-P2 does not prevent fluorescence transitions attributed to catalytic substrate binding. The marked synergistic inhibition of FBPasec by AMP and F-2,6-P2 appears to arise via AMP's promotion of F-2,6-P2 binding. Based on the X-ray crystal structure of porcine kidney FBPase our modelling studies suggest the existence of a distinct F-1,6-P2/F-2,6-P2 inhibitory binding site which partially overlaps with the enzyme's catalytic site. We propose that a pronounced allosteric transition mediated by AMP binding increases access of F-1,6-P2 and F-2,6-P2 to this common inhibitory binding site.

Adenosine Monophosphate↗
PubMed2000

Analysis of sugar metabolism in an EPS producing Lactococcus lactis by 31P NMR.

Sugar metabolism and exopolysaccharide (EPS) production was analysed in Lactococcus lactis by in vivo 31P NMR. Transient production of several sugar phosphates, transient depletion of intracellular phosphate, transient production of ATP and UTP, transient acidification of the medium and alkalinisation of the cytoplasm could be observed in a period of 20 min upon energization by the addition of glucose. EPS and non-EPS producing variants showed similar NMR spectra, the exception being two pH-dependent resonances observed in the former. They were already observed before addition of glucose and their response to glucose incubation reflected exposure to the medium. They are presumably phosphorylated poly- or oligosaccharides being loosely adhered to cell walls. By freezing and perchloric acid extraction of the cell material, different types of phosphorylated compounds could be recognised in the NMR spectra such as fructose-1-6-diphosphate, nucleotides (like ADP, ATP, UTP and TDP) and several nucleotide sugars. The ongoing work is focused on identifying the unknown peaks and quantifying the differences between wild-type cells and the EPS producing variant.

Adenosine Diphosphate↗
PubMed1985

Sulfonylurea stimulates liver fructose-2,6-bisphosphate formation in proportion to its hypoglycemic action.

The effects of 5 sulfonylureas on fructose-2,6-bisphosphate (F-2,6-P2) formation using isolated perfused rat liver were examined. All sulfonylureas examined stimulated dose-dependent formation of the activator in a limited range of the concentration. A maximum effect on F-2,6-P2 formation was observed at the concentration of 10(-3) M of tolbutamide or chlorpropamide, at 10(-4) M of gliclazide or acetohexamide and at 10(-6) M of glibenclamide. These concentrations of sulfonylurea correspond with those in blood when therapeutical doses of the drug are administered orally. Sulfonamide and biguanide did not show any stimulatory effect on F-2,6-P2 level. The results demonstrate that stimulation of liver F-2,6-P2 formation is a common characteristic of sulfonylureas and suggest strongly that one of the extrapancreatic actions of sulfonylurea is stimulation of F-2,6-P2 formation followed by enhancement of glycolysis and inhibition of gluconeogenesis in the liver.

Acetohexamide↗
PubMedDate not supplied

Tolbutamide and insulin stimulation of fructose-2,6-bisphosphate formation in hepatocytes differ.

The effects of tolbutamide and pancreatic hormones on liver fructose-2,6-bisphosphate (F-2,6-P2) formation were examined using isolated rat hepatocytes. Glucagon decreased the F-2,6-P2 level in a dose-dependent manner. Insulin (greater than 10(-9) M) increased the F-2,6-P2 level reduced by glucagon (less than 10(-9) M), but did not show a stimulatory effect on this activator formation in the absence of glucagon. On the other hand, tolbutamide increased the F-2,6-P2 level in hepatocytes regardless of the presence or absence of glucagon. Tolbutamide (2 mM) stimulation on liver F-2,6-P2 formation was enhanced by the concomitant addition of insulin (10(-8) M) in the presence of glucagon (3 X 10(-11) M). These observations suggest that the regulatory effect of tolbutamide on liver F-2,6-P2 level is independent of that of insulin.

Animals↗
PubMed1996

Effect of a novel hypoglycemic agent, KAD-1229 on glucose metabolism and fructose-2,6-bisphosphate content in isolated hepatocytes of normal rats.

The effects of a novel hypoglycemic agent, calcium(2s)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionate dihydrate (KAD-1229), which is a benzyl succinate derivative, on liver metabolism were investigated using isolated hepatocytes from normal rats. In the presence of 10 mM glucose, KAD-1229 increased the L-lactate production (41.1 +/- 0.9 versus 60.9 +/- 2.6 mumol of lactate/g of cells/30 min; P < 0.05) and inhibited gluconeogenesis in hepatocytes (0.94 +/- 0.02 versus 0.70 +/- 0.03 mumol of [2-14C]-pyruvate converted to glucose/g of cells/20 min; P < 0.05). These effects by KAD-1229 were accompanied by an increase in the cellular content of fructose-2,6-bisphosphate (F-2,6-P2), which is one of the important regulators of hepatic glucose metabolism, in a dose-dependent manner (0.05-2.5 mM). KAD-1229 also stimulated the oxidation of [2-14C]-pyruvate and [6-14C]-glucose in the tricarboxylic acid cycle (+18 and +31%, respectively), indicating that stimulation of tricarboxylic acid cycle activity and/or enhancement of the glycolytic flux rate had occurred. Moreover, KAD-1229 did not modify the activities of 6-phosphofructo 2-kinase or fructose-2,6-bisphosphatase, but increased significantly the accumulation of fructose 6-phosphate in hepatocytes. These results suggest that KAD-1229 has extrapancreatic effects on hepatic glucose metabolism, that its actions are mediated through the inhibition of fructose-1,6-bisphosphatase and stimulation of both the 6-phosphofructo 1-kinase reaction and tricarboxylic acid cycle activity by increasing the F-2,6-P2 content in hepatocytes, and that these multiple effects may account in part for the ability of KAD-1229 to reduce blood glucose levels in vivo.

Analysis of Variance↗
PubMed1993

Fructose-1,6-diphosphate fails to limit early myocardial infarction size in a canine model.

STUDY OBJECTIVE: Fructose-1,6-diphosphate (FDP) appears to improve early post-myocardial infarction hemodynamics and limit early myocardial infarct size in previous canine studies. However, these studies did not account for the effect of collateral blood flow on infarct size. Our objective was to determine the effect of FDP on early infarct size and hemodynamics while measuring regional myocardial blood flow. DESIGN: A prospective, blinded, placebo-controlled laboratory study using a canine open-chest left anterior descending coronary artery (LAD) occlusion model. INTERVENTIONS: Twenty-two mongrel dogs were assigned randomly to receive either FDP (175 mg/kg, then 2 mg/kg/min for two hours) or placebo, beginning five minutes after LAD occlusion. MEASUREMENTS AND MAIN RESULTS: Regional myocardial blood flow, hemodynamics, and myocardial infarct size were determined. Infarct size was assessed using magnetic resonance imaging in a subset of animals. Three of the 22 dogs had no infarct and significantly higher collateral blood flow than the 19 animals with myocardial infarction (P < .001). Four hours after LAD occlusion, cardiac index, dP/dtmax, heart rate, and systolic and mean aortic pressures were not statistically different between groups. Infarct size expressed as area of necrosis/area at risk was similar between groups (FDP, 0.55 +/- 0.28; controls, 0.59 +/- 0.31). CONCLUSION: FDP given after occlusion of the LAD in this canine model did not limit early myocardial infarct size.

Animals↗
PubMed1986

Hemodynamics and metabolic effects of fructose 1-6 diphosphate in ischemia and shock--experimental and clinical observations.

Numerous interventions have been used to protect organ systems and cellular viability from the lethal injury accompanying hypoperfusion and ischemia. Some measures have been directed toward improving perfusion, while others have attempted to enhance the metabolic processes. Our work has focused for the most part on augmenting the anaerobic carbohydrate utilization in ischemic and hypoperfused tissues with fructose-1,6-diphosphate (FDP). Such an approach is based on the premise that exogenous FDP will restore the activity of glycolysis, which has been inhibited by acidosis, by intervening in the Embden-Meyerhoff pathway both as a metabolic regulator and as a high-energy substrate. We have tested this hypothesis in more than 1,000 animals subjected to shock or regional ischemia, and the results appear to confirm our presumption. In myocardial infarction, FDP improves hemodynamic parameters, attenuates ECG-proven ischemic injury and dysrhythmias, prevents ATP and creatine phosphate depletion from ischemic myocardium, reduces infarct size, and increases survival. In hemorrhagic, traumatic, and endotoxin shock, FDP improves hemodynamics, attenuates organ injury, and increases survival. Recently we demonstrated that FDP attenuates the reperfusion ischemic tissue injury by inhibiting the generation of oxygen free radicals by neutrophils. In normal volunteers, this agent increases carbohydrate utilization, while administration of a like amount of glucose produces no effect. In patients with myocardial infarction, FDP appears to have the same effect as that observed in the animal model. When this agent is administered to patients in traumatic, hemorrhagic, or septic shock, hemodynamic and pulmonary function are significantly improved. In patients with adult respiratory distress syndrome, similar beneficial effects have been observed with FDP administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2003

Characterization of myoglobin toxicity in renal cortical slices from Fischer 344 rats.

Rhabdomyolysis is associated with acute renal failure. The following study first characterized myoglobin in vitro toxicity using renal cortical slices isolated from male Fischer 344 rats. This model provided interaction between various cells within the nephron and provides myoglobin access predominantly through the basolateral membrane. Second, this study examined the effect of deferoxamine (DFX) and glutathione on myoglobin toxicity to determine the role of radicals and iron. Renal cortical slices were incubated for 30-120 min with 0, 4, 10 or 12 mg/ml myoglobin. Myoglobin was pretreated with 4 mM ascorbic acid prior to addition to the slices to ensure that myoglobin was in its reduced state. In other experiments tissues were pretreated for 15 min with 0.1 mM of the iron chelator DFX or 30 min with 1 mM glutathione prior to co-incubation with myoglobin. Finally, slices were pretreated with 1 mM glutathione for 30 min, rinsed and incubated only with myoglobin. Early event changes occurred within a 60 min exposure and included a decline in pyruvate-stimulated gluconeogenesis, increased lipid peroxidation levels and decreased glutathione levels. Loss of ATP levels and increased lactate dehydrogenase (LDH) release required a 120 min exposure to myoglobin. DFX reduced myoglobin induced effects on LDH leakage but had no effect on gluconeogenesis suggesting that myoglobin toxicity had an iron dependent (LDH) and independent (gluconeogenesis) pathway. Pretreatment with glutathione provided complete protection and was mediated by intracellular events.

Adenine Nucleotides↗
PubMed2003

Characterization of myoglobin toxicity in renal cortical slices from Fischer 344 rats.

Rhabdomyolysis is associated with acute renal failure. The following study first characterized myoglobin in vitro toxicity using renal cortical slices isolated from male Fischer 344 rats. This model provided interaction between various cells within the nephron and provides myoglobin access predominantly through the basolateral membrane. Second, this study examined the effect of deferoxamine (DFX) and glutathione on myoglobin toxicity to determine the role of radicals and iron. Renal cortical slices were incubated for 30-120 min with 0, 4, 10 or 12 mg/ml myoglobin. Myoglobin was pretreated with 4 mM ascorbic acid prior to addition to the slices to ensure that myoglobin was in its reduced state. In other experiments tissues were pretreated for 15 min with 0.1 mM of the iron chelator DFX or 30 min with 1 mM glutathione prior to co-incubation with myoglobin. Finally, slices were pretreated with 1 mM glutathione for 30 min, rinsed and incubated only with myoglobin. Early event changes occurred within a 60 min exposure and included a decline in pyruvate-stimulated gluconeogenesis, increased lipid peroxidation levels and decreased glutathione levels. Loss of ATP levels and increased lactate dehydrogenase (LDH) release required a 120 min exposure to myoglobin. DFX reduced myoglobin induced effects on LDH leakage but had no effect on gluconeogenesis suggesting that myoglobin toxicity had an iron dependent (LDH) and independent (gluconeogenesis) pathway. Pretreatment with glutathione provided complete protection and was mediated by intracellular events.

Adenine Nucleotides↗