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PubMed1999

Glycolytic enzyme activity in hypotonically treated boar spermatozoa.

Treatment of washed boar sperm with hypotonic phosphate buffer disrupted the cytoplasmic membrane and released the soluble contents and phosphofructokinase, but the other glycolytic enzymes and lactate dehydrogenase were retained. Addition of the appropriate substrates and co-factor(s) to preparations of treated cells in phosphate-buffered saline showed that enzyme activity could be re-instated. This simple preparation should be of assistance in the investigation of specific sections of the glycolytic pathway without the use of chemical inhibitors.

Adenosine Diphosphate↗
PubMed1991

Metabolism of fructose-1,6-bisphosphate by mature boar spermatozoa.

Mature epididymal boar spermatozoa converted glucose and fructose to carbon dioxide and lactate and maintained high concentrations of ATP. In the presence of (S)-alpha-chlorohydrin these processes were inhibited and there was an accumulation of fructose-1,6-bisphosphate and dihydroxyacetone phosphate. With fructose-1,6-bisphosphate as the substrate, the concentration of ATP was maintained, carbon dioxide was evolved and dihydroxyacetone phosphate accumulated. Cells pre-incubated with (S)-alpha-chlorohydrin did not maintain ATP levels, evolved less carbon dioxide and produced dihydroxyacetone phosphate. Assays of incubates in which fructose-1,6-bisphosphate was used as the substrate showed the presence of equilibrium quantities of fructose-6-phosphate and glucose-6-phosphate which were not detected when either fructose or glucose were used as substrates. [14C]Fructose and [14C]glucose were not produced from [14C]fructose-1,6-bisphosphate in spermatozoal incubates which had or had not been pre-incubated with (S)-alpha-chlorohydrin. Evidence is presented that a high concentration of fructose-1,6-bisphosphate leads to the formation of fructose-6-phosphate and glucose-6-phosphate but not of fructose and/or glucose.

Adenosine Diphosphate↗
PubMed2002

Inhibition of macrophage migration inhibitory factor (MIF) tautomerase and biological activities by acetaminophen metabolites.

The cytokine macrophage migration inhibitory factor (MIF) has emerged to be an important regulator of the inflammatory response and is critically involved in the development of septic shock, arthritis, and glomerulonephritis. Although the biological activities of MIF are presumed to require a receptor-based mechanism of action, the protein is also a tautomerase and has a catalytically active N-terminal proline that is invariant in structurally homologous bacterial isomerases. This observation raises the possibility that MIF may exert its biological action via an enzymatic reaction. Physiologically relevant substrates for MIF have not been identified, nor have site-directed mutagenesis studies consistently supported the requirement for a functional catalytic site. Small molecule inhibitors of MIF's isomerase activity also have been developed, but none have been shown yet to inhibit MIF biological activity. We report herein that the iminoquinone metabolite of acetaminophen, N-acetyl-p-benzoquinone imine (NAPQI), inhibits both the isomerase and the biological activities of MIF. The reaction between NAPQI and MIF is covalent and produces a NAPQI-modified MIF species with diminished cell binding activity and decreased recognition by anti-MIF mAb. These data are consistent with a model by which the NAPQI reacts with the catalytic Pro-1 of MIF to disrupt the integrity of epitope(s) critical to MIF's biological activity and point to the importance of the catalytic domain, but not the catalytic activity per se, in MIF function. These results also point to a powerful approach for the design of small molecule inhibitors of MIF based on interaction with its catalytic site and constitute an example of a pharmacophore capable of irreversibly inhibiting the action of a proinflammatory cytokine.

Acetaminophen↗
PubMed2000

Compartmentation protects trypanosomes from the dangerous design of glycolysis.

Unlike in other organisms, in trypanosomes and other Kinetoplastida the larger part of glycolysis takes place in a specialized organelle, called the glycosome. At present it is impossible to remove the glycosome without changing much of the rest of the cell. It would seem impossible, therefore, to assess the metabolic consequences of this compartmentation. Therefore, we here develop a computer experimentation approach, which we call computational cell biology. A validated molecular kinetic computer replica was built of glycolysis in the parasite Trypanosoma brucei. Removing the glycosome membrane in that replica had little effect on the steady-state flux, which argues against the prevalent speculation that glycosomes serve to increase flux by concentrating the enzymes. Removal of the membrane did cause (i) the sugar phosphates to rise to unphysiologically high levels, which must have pathological effects, and (ii) a failure to recover from glucose deprivation. We explain these effects on the basis of the biochemical organization of the glycosome. We conclude (i) that the glycosome protects trypanosomes from the negative side effects of the "turbo" structure of glycolysis and (ii) that computer experimentation based on solid molecular data is a powerful tool to address questions that are not, or not yet, accessible to experimentation.

Adenosine Triphosphate↗
PubMed2003

Modifying the stereochemistry of an enzyme-catalyzed reaction by directed evolution.

Aldolases have potential as tools for the synthesis of stereochemically complex carbohydrates. Here, we show that directed evolution can be used to alter the stereochemical course of the reaction catalyzed by tagatose-1,6-bisphosphate aldolase. After three rounds of DNA shuffling and screening, the evolved aldolase showed an 80-fold improvement in k(cat)/K(m) toward the non-natural substrate fructose 1,6-bisphosphate, resulting in a 100-fold change in stereospecificity. (31)P NMR spectroscopy was used to show that, in the synthetic direction, the evolved aldolase catalyzes the formation of carbon-carbon bonds with unnatural diastereoselectivity, where the >99:<1 preference for the formation of tagatose 1,6-bisphosphate was switched to a 4:1 preference for the diastereoisomer, fructose 1,6-bisphosphate. This demonstration is of considerable significance to synthetic chemists requiring efficient syntheses of complex stereoisomeric products, such as carbohydrate mimetics.

Aldehyde-Lyases↗
PubMed2002

Elucidating the biosynthesis of 2-carboxyarabinitol 1-phosphate through reduced expression of chloroplastic fructose 1,6-bisphosphate phosphatase and radiotracer studies with 14CO2.

2-carboxyarabinitol 1-phosphate limits photosynthetic CO2 assimilation at low light because it is a potent, naturally occurring inhibitor of ribulose 1,5-bisphosphate carboxylase/oxygenase. Evidence is presented that this inhibitor is derived from chloroplastic fructose 1,6-bisphosphate. First, transgenic plants containing decreased amounts of chloroplastic fructose 1,6-bisphosphate phosphatase contained increased amounts of fructose 1,6-bisphosphate and 2-carboxyarabinitol 1-phosphate and greatly increased amounts of the putative intermediates hamamelose and 2-carboxyarabinitol, which in some cases were as abundant as sucrose. Second, French bean leaves in the light were shown to incorporate 14C from 14CO2 sequentially into fructose 1,6-bisphosphate, hamamelose bisphosphate, hamamelose monophosphate, hamamelose, and 2-carboxyarabinitol. As shown previously, 14C assimilated by photosynthesis was also incorporated into 2-carboxyarabinitol 1-phosphate during subsequent darkness.

Carbon Dioxide↗
PubMed1978

31P nuclear magnetic resonance studies of bioenergetics and glycolysis in anaerobic Escherichia coli cells.

31P nuclear magnetic resonance spectra of glycolyzing, anaerobic Escherichia coli cells and their perchloric acid extracts were obtained at 145.7 MHz. Time-dependent intracellular concentrations of nucleoside di- and triphosphates, Pi, and sugar phosphates were measured during glycolysis with 2-min resolution, while intracellular and extra-cellular pH values were monitored simultaneously. Upon glucose addition, anaerobic E. coli cells rapidly produce acids and develop a transmembrane pH gradient (delta pH). Glycolysis rates were calculated from the changes in the external pH. It was found that glycolysis rates are strongly dependent on internal pH, sharply decreasing when the pH drops below approximately 7.2. The ATPase inhibitor, dicyclohexylcarbodiimide (DCCD), prevented NTP hydrolysis and inhibited delta pH formation. The uncoupler, carbonyl cyanide p-triflouromethoxyphenyl hydrazone (FCCP), drastically reduced both the delta pH and the NTP level. When the cells were previously treated with DCCD, FCCP collapsed the delta pH while the NTP levels remained high. It is concluded that ATP produced by glycolysis is hydrolyzed by the membrane ATPase to generate a delta pH and that FCCP stimulates ATP hydrolysis by ATPase and collapses the proton gradient.

Anaerobiosis↗
PubMed1979

13C nuclear magnetic resonance studies of anaerobic glycolysis in suspensions of yeast cells.

Anaerobic glycolysis in Saccharomyces cerevisiae has been studied by 13C NMR at 90.5 MHz. [1-13c]Glucose and [6-13C]glucose were fed to suspensions of yeast cells. Time courses for concentration changes of the starting material, of courses for concentration changes of the starting material, of the intermediate fructose 1,6-bisphosphate (Fru-P2), and of the end products, ethanol and glycerol, have been followed with 1-min time resolution. The glucose uptake was well fitted by a Michaelis-Menten model, assuming competition of alpha- and beta-glucose for the same site. The Km for the uptake was found to be 10 mM for beta-glucose and 5 mM for alpha-glucose. The concentration of Fru-P2 showed an initial oscillation before it reached a co,stant level. The 13C label, introduced only as [-13C]- or [6-13C]glucose, was observed in Fru-P2 in both the C1 and C6 positions, simultaneously. From the relative intensities of the C1 Fru-P2 and C6 Fru-P2 peaks in the presence of [1-13C]- and [6-13C]glucose, in vivo kinetic information was obtained about the aldolase-triosephosphate isomerase triangle. We found that under the conditions of these experiments the ratios of backward to forward velocities through aldolase and triosephosphate isomerase were 0.9 +/- 0.1 and 0.8 +/- 1, respectively, indicating they were close to equilibrium.

Anaerobiosis↗
PubMed1981

Inhibition of fructose-1,6-bisphosphatase by fructose 2,6-biphosphate.

Fructose 2,6-bisphosphate, a known powerful stimulator of phosphofructokinase [Van Schaftingen, E., Hue, L. & Hers, H.-G. (1980) Biochem. J. 192, 897-901] was found to inhibit, at micromolar concentrations, liver and muscle fructose-1,6-biphosphate (D-fructose-1,6-bisphosphate 1-phosphohydrolase, EC 3.1.3.11). The main characteristics of this inhibition are that (i) it is much stronger at low than at high substrate concentrations, (ii) it changes the substrate saturation curve from almost hyperbolic to sigmoidal, and (iii) it is synergistic with the inhibition by AMP. This inhibition may play an important role in the stimulation of gluconeogenesis by glucagon, because this hormone is known to decrease the concentration of fructose 2,6-bisphosphate in the liver [Van Schaftingen, E., Hue, L. & Hers, H.-G. (1980) Biochem. J. 192, 887-895].

Adenosine Monophosphate↗
PubMed1981

Control of liver 6-phosphofructokinase by fructose 2,6-bisphosphate and other effectors.

Rat liver 6-phosphofructokinase (ATP-D-fructose-6-phosphate 1-phosphotransferase, EC 2.7.1.11) was partially purified free of interfering enzymes by a rapid procedure. Fructose 2,6-bisphosphate, at micromolar concentrations, greatly stimulated the enzyme by increasing its affinity for fructose 6-phosphate and relieving the inhibition by ATP. Its action was synergistic with that of AMP. As a stimulator of liver phosphofructokinase, fructose 2,6-bisphosphate was approximately 1000- and 2500-fold more efficient than fructose 1,6-bisphosphate and glucose 1,6-bisphosphate, respectively. The concentration at which a half-maximal effect was obtained with the hexose bisphosphates was dependent upon the experimental conditions. It was relatively high at physiological concentrations of substrates, AMP, and Pi, and under these conditions the positive effect of fructose 1,6-bisphosphate was no longer detectable. This was probably due to the negative effect of fructose 1,6-bisphosphate as a reaction product inhibitor. It is concluded that fructose 2,6-bisphosphate rather than fructose 1,6-bisphosphate controls, in association with other effectors, the activity of phosphofructokinase in the liver.

Adenosine Monophosphate↗
PubMed1981

Oscillations and control features in glycolysis: analysis of resonance effects.

We have presented [Termonia, Y. & Ross, J. (1981) Proc. Natl. Acad. Sci. USA 78, 2952-2956] an analysis of glycolysis based on experimental findings. Here, we give an interpretation based on the concepts of efficiency, resonance response, and control features available to highly nonlinear reaction kinetics. The comprehensive model of glycolysis, for which we presented numerical evaluation of concentration oscillations, entropy production, and average ATP/ADP ratios is separated into two subsystems: one for the phosphofructokinase (PFKase) reaction, the other for the pyruvate kinase (PKase) reaction. We analyze each subsystem separately and find that, for a range of parameter values around the best estimates obtained from experimental data, the PFKase reaction exhibits sustained oscillations. The PKase reaction, on the other hand, is in a stable stationary state and shows an oscillatory relaxation. The period of the PFKase reaction is within 25% of that obtained by computer simulation of the full model. Moreover, if, for a given set of kinetic parameters, the period of the oscillations in the PFKase reaction is of the same order of magnitude as the period of the oscillatory relaxation of the PKase reaction, then the onset of oscillatory behavior past marginal stability forces a tuning of the PFKase reaction period to that of the PKase reaction. Thus, the PKase reaction tunes the frequency of the primary oscillophor, the PFKase reaction, so that a resonance response results in the PKase reaction. We find this result for a substantial range of parameters. The sharp increase in the ATP/ADP ratio and the decrease in the dissipation (entropy production) are seen to be a result of the forced tuning to resonance. The origin of the remarkable control feature of the tuning of one part of the pathway by another that follows in the reaction mechanism is the coupling of the two parts and, in the case of glycolysis, this is realized by the intermediate fructose 1,6-diphosphate, which participates crucially in the PFKase and PKase reactions.

Adenine Nucleotides↗
PubMed1982

Regulation of 6-phosphofructo-2-kinase activity by cyclic AMP-dependent phosphorylation.

Addition of glucagon to isolated rat hepatocytes resulted in inhibition of 6-phosphofructo-2-kinase (ATP:D-fructose-6-phosphate-2-phosphotransferase) activity in extracts of the cells and in a decrease in the intracellular level of fructose 2,6-bisphosphate. The effect on 6-phosphofructo-2-kinase was characterized by a decrease in the affinity of the enzyme for fructose 6-phosphate. To investigate the mechanism of action of glucagon, 6-phosphofructo-2-kinase from rat liver was partially purified by polyethylene glycol precipitation, DEAE-cellulose chromatography, (NH4)2SO4 fractionation, Sephacryl S-200 gel filtration, DEAE-Sephadex chromatography, and Sephadex G-100 gel filtration. Incubation of the purified enzyme with the catalytic subunit of the cyclic AMP-dependent protein kinase from rat liver and [gamma-32P]ATP resulted in 32P incorporation into a protein with a subunit Mr of 49,000 as determined by NaDodSO4 disc gel electrophoresis. Associated with this phosphorylation was an inhibition of 6-phosphofructo-2-kinase activity that was also characterized by a decrease in the affinity of the enzyme for fructose-6-phosphate. Both the phosphorylation and the inhibition of the purified 6-phosphofructo-2-kinase were blocked by addition of the heat-stable protein kinase inhibitor. It is concluded that the glucagon-induced decrease in fructose 2,6-bisphosphate levels observed in isolated hepatocytes is due, at least in part, to cyclic AMP-dependent phosphorylation and inhibition of 6-phosphofructo-2-kinase.

Animals↗
PubMed1982

Regulation of fructose-6-phosphate 2-kinase by phosphorylation and dephosphorylation: possible mechanism for coordinated control of glycolysis and glycogenolysis.

The kinetic properties and the control mechanism of fructose-6-phosphate 2-kinase (ATP: D-fructose-6-phosphate 2-phosphotransferase) were investigated. The molecular weight of the enzyme is approximately 100,000 as determined by gel filtration. The plot of initial velocity versus ATP concentration is hyperbolic with a Km of 1.2 mM. However, the plot of enzyme activity as a function of fructose-6-phosphate is sigmoidal. The apparent K0.5 for fructose-6-phosphate is 20 microM. Fructose-6-phosphate 2-kinase is inactivated by the catalytic subunit of cyclic AMP-dependent protein kinase, and the inactivation is closely correlated with phosphorylation. The enzyme is also inactivated by phosphorylase kinase in the presence of Ca2+ and calmodulin. The phosphorylated fructose-6-phosphate 2-kinase, which is inactive, is activated by phosphorylase phosphatase and alkaline phosphatase. The possible physiological significance of these observations in the coordinated control of glycogen metabolism and glycolysis is discussed.

Calcium↗
PubMed1983

Regulation of carbohydrate metabolism by 2,5-anhydro-D-mannitol.

In hepatocytes isolated from fasted rats, 2,5-anhydromannitol inhibits gluconeogenesis from lactate plus pyruvate and from substrates that enter the gluconeogenic pathway as triose phosphate. This fructose analog has no effect, however, on gluconeogenesis from xylitol, a substrate that enters the pathway primarily as fructose 6-phosphate. The sensitivity of gluconeogenesis to 2,5-anhydromannitol depends on the substrate metabolized; concentrations of 2,5-anhydromannitol required for 50% inhibition increase in the order lactate plus pyruvate less than dihydroxyacetone less than glycerol less than sorbitol less than fructose. The inhibition by 2,5-anhydromannitol of gluconeogenesis from dihydroxyacetone is accompanied by an increase in lactate formation and by two distinct crossovers in gluconeogenic-glycolytic metabolite patterns-i.e., increases in pyruvate concentrations with decreases in phosphoenolpyruvate and increases in fructose-1,6-bisphosphate concentrations with little change in fructose 6-phosphate. In addition, 2,5-anhydromannitol blocks the ability of glucagon to stimulate gluconeogenesis and inhibit lactate production from dihydroxyacetone. 2,5-Anhydromannitol decreases cellular fructose 2,6-bisphosphate content in hepatocytes; therefore the effects of the fructose analog are not mediated by fructose 2,6-bisphosphate, a naturally occurring allosteric regulator. 2,5-Anhydromannitol also inhibits gluconeogenesis in hepatocytes isolated from fasted diabetic rats, but higher concentrations of the analog are required.

Animals↗
PubMed1985

Phorbol 12-myristate 13-acetate and insulin increase the concentration of fructose 2,6-bisphosphate and stimulate glycolysis in chicken embryo fibroblasts.

Incubation of chicken embryo fibroblasts with mitogenic concentrations of insulin for 24 hr or with the tumor promoter phorbol 12-myristate 13-acetate for 6 hr stimulated lactate release and 3-O-methylglucose uptake. Insulin also increased the Vmax of 6-phosphofructo-1-kinase (ATP:D-fructose-6-phosphate 1-phosphotransferase, EC 2.7.1.11). Both agents increased the concentration of fructose 2,6-bisphosphate and the activity of 6-phosphofructo-2-kinase (EC 2.7.1.-), the enzyme that catalyzes the synthesis of this stimulator of 6-phosphofructo-1-kinase. These changes provide an explanation for the stimulation of glycolysis by insulin and phorbol esters. In contrast to the situation in rat liver, fructose 2,6-bisphosphate concentration did not decrease after cyclic AMP treatment. Incubation of cells with phorbol ester analogues or with glycerol derivatives that are known to stimulate, or to bind to, protein kinase C did increase the concentration of fructose 2,6-bisphosphate, suggesting that the stimulation of 6-phosphofructo-2-kinase by phorbol 12-myristate 13-acetate is mediated by protein kinase C.

3-O-Methylglucose↗
PubMed1992

Crystal structure of the neutral form of fructose 1,6-bisphosphatase complexed with regulatory inhibitor fructose 2,6-bisphosphate at 2.6-A resolution.

The three-dimensional structure of the complex between fructose 1,6-bisphosphatase (EC 3.1.3.11) and the physiological inhibitor beta-D-fructose 2,6-bisphosphate (Fru-2,6-P2), an analogue of the substrate (fructose 1,6-bisphosphate), has been refined at 2.6-A resolution to a residual error (R) factor of 0.171. The rms deviations are 0.012 A and 2.88 degrees from ideal geometries of bond lengths and angles, respectively. The Fru-2,6-P2 occupies the active sites of both polypeptides C1 and C2 in the crystallographic asymmetric unit in the space group P3(2)21. The furanose and 6-phosphate of Fru-2,6-P2 are located at the fructose 6-phosphate site established earlier, and the 2-phosphate binds to the OH of Ser-124, the NH3+ of Lys-274, and the backbone NH of Gly-122 and Ser-123. Backbone displacements of 1 A occur for residues from Asp-121 to Asn-125. Model building of substrate alpha-D-Fru-1,6-P2 based on the binding structure of Fru-2,6-P2 in the active site shows interactions of the 1-phosphate with the backbone NH of Ser-123 and Ser-124. In the AMP sites, density peaks attributed to Fru-2,6-P2 are seen in C1 (and C4) but not in C2 (and C3). This minor binding of Fru-2,6-P2 to AMP sites partially explains the synergistic interaction between AMP and Fru-2,6-P2 and the protection of the AMP site from acetylation in the presence of Fru-2,6-P2. In the synergistic interaction between AMP and Fru-2,6-P2, inhibition of catalytic metal binding by the presence of Fru-2,6-P2 at the active site, and propagation of structural changes over some 28 A along beta-strand B3 from residues 121 to 125 in the active site to Lys-112 and Tyr-113 in the AMP site, as well as movement of helices across the interdimeric interfaces, may affect AMP binding and the subsequent R-to-T transition. In addition, occupancy of Fru-2,6-P2 at the AMP sites of C1 and C4 may favor binding of AMP to the remaining unoccupied AMP sites and thus promote the accompanying quaternary conformational changes.

Amino Acid Sequence↗
PubMed1993

Characterization of a hepatoma mRNA transcribed from a third promoter of a 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-encoding gene and controlled by ets oncogene-related products.

6-Phosphofructo-2-kinase (EC 2.7.1.105)/fructose-2,6-bis-phosphatase (EC 3.1.3.46) catalyzes the synthesis and degradation of fructose 2,6-bisphosphate, a ubiquitous stimulator of glycolysis. The liver (L-type) and muscle (M-type) mRNAs for this bifunctional enzyme arise from distinct promoters of the same gene. We have now characterized in rat hepatoma FTO2B cells another mRNA, which is transcribed from a third promoter of that gene. This F-type mRNA is present in fetal rat liver and muscle, in rat placenta, and in several established rat cell lines. The F promoter contains no TATA box but contains several binding sites for Sp1 and for members of the ets oncogene family. Transfection of FTO2B cells with constructs containing the intact or mutagenized F promoter showed that its activity depends mainly on one of these sites. This site bound a heteromeric FTO2B cell protein indistinguishable from the ets-related GA binding protein alpha/ankyrin-repeats GA binding protein beta transcription factor.

Animals↗
PubMed1994

Crystal structure of fructose-1,6-bisphosphatase complexed with fructose 2,6-bisphosphate, AMP, and Zn2+ at 2.0-A resolution: aspects of synergism between inhibitors.

The crystal structure of fructose-1,6-bisphosphatase (Fru-1,6-Pase; EC 3.1.3.11) complexed with Zn2+ and two allosteric regulators, AMP and fructose 2,6-bisphosphate (Fru-2,6-P2) has been determined at 2.0-A resolution. In the refined model, the crystallographic R factor is 0.189 with rms deviations of 0.014 A and 2.8 degrees from ideal geometries for bond lengths and bond angles, respectively. A 15 degrees rotation is observed between the upper dimer C1C2 and the lower dimer C3C4 relative to the R-form structure (fructose 6-phosphate complex), consistent with that expected from a T-form structure. The major difference between the structure of the previously determined Fru-2,6-P2 complex (R form) and that of the current quaternary T-form complex lies in the active site domain. A zinc binding site distinct from the three binding sites established earlier was identified within each monomer. Helix H4 (residues 123-127) was found to be better defined than in previously studied ligated Fru-1,6-Pase structures. Interactions between monomers in the active site domain were found involving H4 residues from one monomer and residues Tyr-258 and Arg-243 from the adjacent monomer. Cooperativity between AMP and Fru-2,6-P2 in signal transmission probably involves the following features: an AMP site, the adjacent B3 strand (residues 113-118), the metal site, the immediate active site, the short helix H4 (residues 123-127), and Tyr-258 and Arg-243 from the adjacent monomer within the upper (or lower) dimer. The closest distance between the immediate active site and that on the adjacent monomer is only 5 A. Thus, the involvement of H4 in signal transmission adds another important pathway to the scheme of the allosteric mechanism of Fru-1,6-Pase.

Adenosine Monophosphate↗