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At least 631 records · Page 35Linked to original sources
PubMed1983

Ca2+-dependent stimulation of hexose transport by A23187, 12-O-tetradecanoylphorbol-13-acetate and epidermal growth factor in mouse fibroblasts.

Ca2+ ionophore A23187 stimulated 2-deoxy-D-glucose (2DG) uptake in Swiss 3T3 mouse fibroblasts. Chelation of extracellular Ca2+ with ethylene-glycol-bis-(beta-aminoethylether) N,N'-tetraacetic acid (EGTA) inhibited the effect of A23187. Similarly, the stimulation of 2DG uptake by a tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) was prevented by EGTA, whereas the epidermal growth factor (EGF)-stimulated 2DG uptake was not affected by EGTA alone, but in the presence of both EGTA and A23187 which effectively depleted cellular Ca2+ content, EGF could no longer stimulate 2DG uptake. These results suggest that Ca2+ regulates hexose transport system in Swiss 3T3 mouse fibroblasts, the activation of which by TPA and EGF differently depends on Ca2+.

Animals↗
PubMed1984

Nitroheterocycle metabolism in mammalian cells. Stimulation of the hexose monophosphate shunt.

Misonidazole, SR-2508, nitrofurazone and other nitroheterocycles stimulated release of 14CO2 from [1-14C]glucose but not from [6-14C]glucose when incubated with mouse Ehrlich ascites cells or human A549 lung carcinoma cells in vitro. This demonstrated that the nitro compounds activated the hexose monophosphate shunt and is evidence that an important pathway of nitro reduction in these cell lines is electron transfer from NADPH-dependent cytochrome c reductase to the nitro group. Shunt activity was stimulated under both aerobic and anaerobic conditions. For catalase-free Ehrlich cells, aerobic effects were greater than anaerobic, indicating that NADPH was used for reduction of H2O2, via GSH peroxidase and reductase, as well as for one-electron nitro reduction, under aerobic conditions. Several of the compounds tested stimulated 14CO2 release from [2-14C]glucose as well as from [1-14C]-glucose. This shows that the cellular requirement for NADPH, in the presence of nitro drug, was great enough to cause recycling of pentose phosphates. Recycling could decrease the availability of ribose-5-P needed for nucleic acid synthesis, which could partly explain the inhibition of DNA synthesis observed upon prolonged aerobic incubation of cells with nitro compounds. Comparison of the rate of disappearance of nitrofurazone from anaerobic A549 cell suspensions with the rate of 14CO2 release suggests that the drug reduction in this cell line was catalyzed almost entirely by NADPH-requiring enzymes.

Anaerobiosis↗
PubMed1986

Effects of nine synthetic putative metabolites of primaquine on activity of the hexose monophosphate shunt in intact human red blood cells in vitro.

Suspensions of washed human red blood cells were treated with nine synthetic putative metabolic derivatives of primaquine (PQ'), and their individual effects on activity of the hexose monophosphate shunt (HMS) were quantitated by radiometric analysis of 14CO2 from [14C] glucose. The most potent HMS stimulant was 5-hydroxy-6-methoxy-8-aminoquinoline (5H6MQ), which caused 10-fold elevation of HMS activity at an estimated concentration of 0.004 mM. Ten millimolar primaquine (PQ) was required to achieve the same effect. Thus, 5H6MQ was approximately 2500-fold more reactive with the HMS than PQ. Other analogs achieved less than 0.4- to 154-fold increases in HMS reactivity. Patterns of effects on HMS activity indicated that 5-hydroxylation and/or N-dealkylation of PQ strongly enhanced HMS reactivity. In contrast, none of the putative metabolites of PQ activated the proteolytic system known to degrade oxidized protein in red cells, indicating that stimulation of the HMS by the PQ analogs was not related to an injurious oxidative stress. Red cells pretreated with 1.0 mM N-ethylmaleimide (NEM) or with 1.0% (w/v) sodium nitrite to cause glutathione sulfhydryl blockage and conversion of red cell hemoglobin to methemoglobin (metHb), respectively, also showed elevation of HMS activity when exposed to 5H6MQ. These observations suggested that 5H6MQ-induced elevation of HMS activity was at least partially independent of glutathione redox reactions, hydrogen peroxide accumulation and reaction with oxyhemoglobin. The relevance of these observations to proposed mechanisms of hemolytic toxicity of PQ is discussed.

Aminoquinolines↗
PubMed1993

Chemical synthesis and kinetic characterization of UDP-2-deoxy-D-lyxo-hexose("UDP-2-deoxy-D-galactose"), a donor-substrate for beta-(1-->4)-D-galactosyltransferase.

Bovine beta-(1-->4)-galactosyltransferase (GalT) transfers galactose from UDP-galactose to beta-D-GlcpNAc-terminating oligosaccharides to produce N-acetyllactosamine sequences. We report here the chemical synthesis, structural characterization and enzymatic evaluation of the very labile UDP-2-deoxy-D-lyxo-hexose ("UDP-2-deoxy-galactose," 2) as an alternate donor for GalT. Donor 2 had kinetic parameters, including a Km value of 51 microM, almost identical to those for the natural substrate UDP-galactose when beta-D-GlcpNAc-O(CH2)8COOMe was used as the acceptor. The product of the enzymatic transfer was isolated and confirmed to have the expected 2'-deoxy-N-acetyllactosamine sequence.

Animals↗
PubMed1994

Synthesis of a hexasaccharide corresponding to part of the heptose-hexose region of the Salmonella Ra core, and a penta- and a tetra-saccharide that compose parts of this structure.

The synthesis of the hexasaccharide 2-(4-trifluoroacetamidophenyl)ethyl O-alpha-D-galactopyranosyl-(1-->3)-[O-alpha-D-galactopyranosyl-(1-->6)]- O-alpha-D-glucopyranosyl-(1-->3)-[O-L-glycero-alpha-D-manno-heptopyranos yl- (1-->7)]-O-L-glycero-alpha-D-manno-heptopyranosyl-(1-->3)-L-glycero-alph a-D- manno-heptopyranoside, corresponding to the heptose and part of the hexose region in the Salmonella Ra core, is described. Syntheses of the pentasaccharide 2-(4-trifluoroacetamidophenyl)ethyl O-alpha-D-galactopyranosyl-(1-->3)-O-alpha-D-glucopyranosyl-(1-->3)-[O-L - glycero-alpha-D-manno-heptopyranosyl-(1-->7)]-O-L-glycero-alpha-D-manno- heptopyranosyl-(1-->3)-L-glycero-alpha-D-manno-heptopyranoside and the tetrasaccharide 2-(4-trifluoroacetamidophenyl)ethyl O-alpha-D-glucopyranosyl-(1-->3)-[O-L-glycero-alpha-D-manno-heptopyranos yl- (1-->7)]-O-L-glycero-alpha-D-manno-heptopyranosyl-(1-->3)-L-glycero-alph a-D- manno-heptopyranoside are also described. Coupling of methyl 2,3,4,6-tetra-O-benzyl-1-thio-beta-D- glucopyranoside and methyl 2-O-benzyl-4,6-O-benzylidene-3-O-(2,3,4,6-tetra-O-benzyl-alpha-D- galactopyranosyl)-1-thio-beta-D-glucopyranoside to a triheptoside derivative with a free HO-3', using dimethyl(methylthio)sulfonium triflate and N-iodosuccinimide-silver triflate as promoters, gave the protected tetra- and penta-saccharide, respectively. Removal of the benzylidene group from the pentasaccharide followed by a regio- and stereo-selective coupling using halide-assisted conditions and 2,3,4,6-tetra-O-benzyl-alpha-D- galactopyranosyl bromide as donor gave the protected hexasaccharide. Deprotection then gave the target structures.

Carbohydrate Conformation↗
PubMed1987

Hexose monophosphate shunt and cholesterogenesis in lead-induced kidney hyperplasia.

De novo cholesterol synthesis and hexose monophosphate (HMP) shunt were studied in rat kidney stimulated to proliferate by a single administration of lead nitrate. Lead-treated rat kidneys showed an increase in DNA synthesis, as measured by [3H]thymidine incorporation starting at 18 h and with a maximum at 24 h. Renal DNA synthesis was preceded by an increase in de novo cholesterol synthesis and an enhancement in the activity of the HMP shunt, as indicated by increased activity of G6PDH and 6PGDH. These findings indicate that enhancement of cholesterol synthesis and of the HMP shunt is closely associated with the active proliferative process induced in the kidney by treatment with lead nitrate.

Animals↗
PubMed1985

Stimulation of the hexose monophosphate pathway by pyrroline-5-carboxylate reductase in the lens.

Addition of pyrroline-5-carboxylate (P5C) or its precursors to rat lenses cultured for 24 hr in TC-199 medium containing 14C-glucose results in an apparent concentration-dependent increase in hexose monophosphate-pentose (HMP) pathway activity. Addition of proline, the reduction product of P5C, did not result in an increase, suggesting that stimulation of the HMP pathway is related to the reduction of P5C to proline by the enzyme P5C reductase. No apparent feedback inhibition on P5C reductase was observed. Stimulation of HMP pathway activity by P5C was also observed in the lenses of Philly and Nakano mouse, two models of congenital osmotic cataracts. Compared with its genetic control, the Swiss--Webster mouse, generally no difference in the lenticular levels of HMP pathway activity was observed in the Philly mouse--even after the onset of cataract. Stimulation of the HMP pathway in the Philly lens by P5C, however, was consistently lower than its control. In the lenses from the Nakano mouse and its genetic control, the Balb/c mouse, no difference in the percentage stimulation of the HMP pathway resulting from the addition of P5C was observed, but HMP pathway activity in the Nakano lens was consistently lower than that of the control.

Aging↗
PubMed1991

Analysis of concurrent glucose consumption by the hexose monophosphate shunt, glycolysis, and the polyol pathway in the crystalline lens.

A method based on 13C-NMR spectroscopy is described, in which the metabolism of [13C2]glucose was assessed in intact rat lenses. By analysing the ratio of 13C3/(13C2 + 13C3) lactate, a quantitative measurement of the hexose monophosphate shunt (HMPS) activity could be derived. Similarly, measurements of the time-dependent increase of lactate and sorbitol permitted the determination of the activity of the Embden-Meyerhof pathway and the polyol pathway, respectively. This method offers significant advantages over other biochemical and spectroscopic methods and allows for the first time a direct correlation between the activities of the polyol pathway and the HMPS.

Animals↗
PubMed1988

Effects of ATP depletion on the mechanism of hexose transport in intact human erythrocytes.

Depletion of ATP is known to inhibit glucose transport in human erythrocytes, but the kinetic mechanism of this effect is controversial. Selective ATP depletion of human erythrocytes by 10 micrograms/ml A23187 in the presence of extracellular calcium inhibited 3-O-methylglucose influx noncompetitively and efflux competitively. ATP depletion also decreased the ability of either equilibrated 3-O-methylglucose or extracellular maltose to inhibit cytochalasin B binding in intact cells, whereas neither total high-affinity cytochalasin B binding nor its Kd was affected. Under the one-site model of hexose transport these data indicate that ATP depletion decreases both the affinity of the inward-facing glucose carrier for substrate and its ability to reorient outwardly in intact cells.

3-O-Methylglucose↗
PubMed1989

The hexose carrier from Chlorella. cDNA cloning of a eucaryotic H+-cotransporter.

The cDNA coding for the inducible H+/hexose cotransporter of Chlorella kessleri has been cloned and sequenced. It was isolated by differential screening of a cDNA library prepared from glucose-induced cells. The increase in expression of the gene correlates quantitatively with the increase in uptake activity due to induction; it is not expressed in a hexose transport mutant. An open reading frame allows for a membrane protein of 533 amino acids with a relative molecular mass of 57 kDa. This protein is highly homologous to the human and rat glucose transporters catalyzing facilitated diffusion and to the bacterial H+/pentose cotransporters. It is not related to the H+/lactose cotransporter of E. colli and to the mammalian Na+/glucose cotransporter.

Base Sequence↗
PubMed1984

An in vitro micro-volume procedure for rapid measurement of erythrocytic hexose monophosphate shunt activity.

A radiometric micro-volume procedure for measurement of erythrocytic hexose monophosphate shunt (HMS) activity in intact cells in vitro is described. The procedure is rapid, allowing 200 individual HMS determinations in a single experiment of 5 hr duration. The procedure is reproducible, yielding HMS activity means insignificantly different (P greater than 0.05) between replicate experiments. A profile of sodium nitrite-induced HMS stimulation is reported: HMS was elevated 2-fold (P less than 0.001) between zero and 2.5 mM NaNO2; HMS elevation was more distinct (7-fold) between 2.5 and 5.0 mM NaNO2; maximum activity (22-fold) was observed between 10 and 20 mM NaNO2; greater than 20 mM NaNO2 caused significant (P less than 0.001) diminution of HMS; glucose carbon recycling through the HMS occurred only with greater than 2.5 mM NaNO2 where this process contributed less than or equal to 16% to total HMS activity.

Adult↗
PubMed1984

Methylene blue-mediated hexose monophosphate shunt stimulation in human red blood cells in vitro: independence from intracellular oxidative injury.

The red blood cell hexose monophosphate shunt (HMS) and proteolytic responses to several concentrations of Methylene Blue or sodium nitrite were measured. The results suggested two distinct mechanisms for activation of the HMS: (1) nitrite treatment increased HMS activity in response to oxidative challenge to red cell protein; (2) Methylene Blue treatment activated HMS without injurious oxidative challenge. Nitrite-treated cells actively degraded protein, whereas Methylene Blue-treated red cells did not activate proteolytic systems that degrade oxidized red cell protein. These observations are relevant to proposed in vitro systems for evaluation of drug hemolytic toxicity potential on the basis of HMS stimulation capacity.

Adult↗
PubMed1995

Kinetic properties of hexose-monophosphate dehydrogenases. I. Isolation and partial purification of glucose-6-phosphate dehydrogenase from rat liver and kidney cortex.

Glucose-6-phosphate dehydrogenase (G6PDH) from rat-liver and kidney-cortex cytosol has been partially purified and almost completely separated from 6-phosphogluconate dehydrogenase activity. The purification and isolation procedures included high-speed centrifugation, 40-55% ammonium sulphate fractionation, by which both enzyme activities were separated, and finally, the application of the protein fraction to a column of Sephadex G-25 equilibrated with 10 mM Tris-EDTA-NADP buffer, pH 7.6, to eliminate any contaminating metabolites. The kinetic properties of isolated liver and renal G6PDH were examined. Both enzymes showed a typical Michaelis-Menten kinetic saturation curve with no evidence of co-operativity. The optimum pH of both liver and kidney cortex G6PDH was 9.4. The Km values for glucose-6-phosphate (G6P) and for NADP were 3.29 x 10(-4) M and 1.00 x 10(-4) M respectively. The specific activity measured at 37 degrees C and optimum pH was 327.1 mU/ mg of protein. NADPH caused a competitive inhibition with a Ki of 10 microM. The Km values for the G6P and NADP of kidney-cortex G6PDH were 2.06 x 10(-4) and 0.25 x 10(-4) M respectively. The specific activity at pH 9.4 and 37 degrees C was 76.55 mU/mg of protein. The Ki value for NADPH inhibition was 4 microM. This work describes an easy, rapid and reliable method for the separation of the two dehydrogenases involved in the hexose-monophosphate shunt in animal tissues.

Animals↗
PubMed1982

The effect of free radical derived hydroxyeicosatetraenoic acids on hexose transport in the human polymorphonuclear leukocyte.

The following racemic hydroxyicosatetraenoic acids were prepared and assayed for their ability to stimulate hexose transport in human polymorphonuclear leukocytes: 15-, 12-, 11-, 9-, 8-, and 5-hydroxyicosatetraenoic acids. The compounds were isolated from reduced, autoxidized arachidonic acid. The results demonstrate that only the 12- and 5-hydroxyicosatetraenoic acids are biologically active inducing half-maximal responses at 820 and 176 nM, respectively. Thus, the bioactions of hydroxicosatetraenoates ae crucially dependent upon the position of the hydroxy residue. Response to both hydroxyicosatetraenoates was effectively blocked by two inhibitors of arachidonic acid metabolism: nordihydroguaiaretic acid and indomethacin. A third arachidonic acid antimetabolite, 5, 8, 11, 14-eicosatetraynoic acid, completely inhibited the response to 12-HETE but caused only partial inhibition of the response to 5-HETE.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1990

Modulation of eicosanoid biosynthesis and inhibition of substrate availability for phospholipase A2 by a modified hexose sugar, amiprilose hydrochloride.

The modified hexose sugar, amiprilose HCl [1,2-O-isopropylinine-3-O-3'-(N',N'-dimethylamino-n-propyl)-D-g lucufuranose hydrochloride], has previously been shown to have antiinflammatory activities. The present study assessed whether eicosanoid biosynthesis is regulated by amiprilose HCl and whether the regulation is influenced at the early stage of arachidonate liberation from the phospholipid by phospholipase A2 (PLA2). Secretion of both prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) by peritoneal macrophages and neutrophils from amiprilose HCl-treated mice was reduced with neutrophils being slightly more sensitive to the inhibitory effects. Amiprilose HCl was less effective in vitro at inhibiting PGE2 and LTB4 secretion that it was in vivo. Amiprilose HCl did not have a direct inhibitory effect on the PLA2 enzyme or on secretion of the soluble form of PLA2. In contrast, amiprilose HCl modulated the phospholipid substrate for PLA2 as there was inhibition of label release from [1-14C]-oleic acid-labeled substrate source (i) when labeled E. coli substrate for pure PLA2 had been preincubated with amiprilose HCl, or (ii) when labeled peritoneal cells, which had been preincubated with amiprilose HCl, were used as a substrate source either for pure PLA2 or for their own PLA2. Amiprilose HCl was found to bind to peritoneal cells rapidly, but transiently, with maximal binding occurring within 5 min at 37 degrees C. Thus, amiprilose HCl was shown to be inhibitory to secretion of PGE2 and LTB4, at least in part, by inhibiting the availability of substrate for PLA2.

Animals↗
PubMed1985

Inhibition of human neutrophil function by 6-aminonicotinamide: the role of the hexose monophosphate shunt in cell activation.

Stimulation of polymorphonuclear leukocytes with phorbol myristate acetate (PMA) or chemotactic factors such as f-Met-Leu-Phe (fMLP) activates a membrane oxidase which results in the generation of the superoxide anion (O2-) and the oxidation of NADPH to NADP+. The subsequent reduction of NADP+ to NADPH is believed to be directly dependent upon activation of the hexose monophosphate shunt (HMPS). To further understand the role of the HMPS in the oxidative burst, we examined the kinetics of HMPS activation by fMLP and PMA. Both of these agents stimulate an increase in HMPS activity that parallels their production of O2-. To examine the role of the HMPS in cell activation, we treated polymorphonuclear leukocytes with the specific HMPS inhibitor, 6-aminonicotinamide. This pretreatment inhibited fMLP- and PMA-stimulated HMPS activity and O2- release by 80% and 60% respectively with a 50% inhibitory dose (ID50) of 5 X l0(-7)M. Measurement of reduced NADPH using 350 nm ultraviolet light-stimulated fluorescence and flow cytometry indicated that 6-aminonicotinamide had no effect on resting levels of NADPH fluorescence but significant inhibited the fluorescence recovery following stimulation with fMLP or PMA. In contrast, PMA- and fMLP-stimulated membrane depolarization measured with the carbocyanine dye 3,3'-dihexyloxacarbocyanine iodide and chemotaxis to fMLP were unaffected by 6-aminonicotinamide treatment. On the contrary, fMLP- or PMA-stimulated myeloperoxidase release by fMLP or PMA was enhanced by 30% and 150%, respectively, following treatment with 6-aminonicotinamide, suggesting a decreased oxidative inactivation of myeloperoxidase.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemotaxis↗
PubMed1994

Hexose-monophosphate shunt activity in intact Plasmodium falciparum-infected erythrocytes and in free parasites.

The hexose monophosphate shunt (HMS) produces NADPH for reductive antioxidant protection and for metabolic regulation, as well as ribose-5-phosphate needed for the synthesis of nucleic acids. Since malaria-infected red blood cells (RBC) are under endogenous oxidant stress, it was interesting to determine HMS activity in intact infected cells, as well as in free parasites. HMS activity was determined by measuring the evolution of 14CO2 from D-[1-14C]glucose in normal RBC, in intact Plasmodium falciparum-infected RBC (IRBC) and in free parasites. The HMS activity of IRBC was found to be 78 times higher than that of normal RBC. This activity increased with parasite maturation from the ring stage toward the trophozoite stage, and declined at the schizont stage. The HMS activity of the parasite contributes 82% of the total observed in the intact IRBC, and that of the host cell is increased some 24-fold. The increased reducing capacity of IRBC and free parasites were also evidenced by the larger ability for reductive accumulation of methylene blue. Since the endogenous oxidative stress is produced by the parasite digestion of the host cell's hemoglobin, inhibition of this process with protease inhibitors, by alkalinization of the parasite's food vacuole, or by the application of antimalarial drugs, resulted in 20-44% inhibition of IRBC HMS activity. A similar inhibition was observed in the presence of scavengers of oxidative radicals, uric and benzoic acids. These inhibitors had only a minor effect on the HMS activity of free parasites. D-[1-14C]glucose and D-[6-14C]glucose contributed equally to newly synthesized nucleic acids, suggesting that ribose-5-phosphate needed for this synthesis is contributed by the non-oxidative activity of HMS. These results imply that a major portion of parasite HMS activity and the activated HMS of the host cell are devoted to counteract the endogenously generated oxidative stress.

Animals↗