Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.1.1 (hexokinase)
 5,274 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Approximately 23% of the glycolytic enzyme aldolase in the perinuclear region of Swiss 3T3 cells is immobile as measured by FRAP. Previous studies suggest that the immobile fraction may be associated with the actin cytoskeleton (Pagliaro, L. and D. L. Taylor. 1988. J. Cell Biol. 107:981-991), and it has been proposed that the association of some glycolytic enzymes with the cytoskeleton could have functional significance, perhaps involving a fundamental relationship between glycolysis, cytoplasmic organization, and cell motility. We have tested the effect of a key glycolytic inhibitor and an actin cytoskeletal modulator on the mobility of aldolase in living cells directly, using fluorescent analog cytochemistry and FRAP. We report here that the competitive hexokinase inhibitor 2-deoxyglucose releases the bound fraction of aldolase in 3T3 cells within 10 min, and that this process is reversible upon washout of the inhibitor. A similar result is produced with the actin-binding agent, cytochalasin D. These results are consistent with models in which glycolytic enzymes are not exclusively diffusion-limited, soluble proteins, but may exist partially in the solid phase of cytoplasm. Such organization has significant implications for both the modulation of cytoplasmic structure and for cellular metabolism.
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PMID:2-Deoxyglucose and cytochalasin D modulate aldolase mobility in living 3T3 cells. 150 Apr 28

1. The action of beryllium on the following enzymes has been examined: alkaline phosphatase (Escherichia coli and kidney), acid phosphatase, phosphoprotein phosphatase, apyrase (potato), adenosine triphosphatase (liver nuclei, liver mitochondria, brain microsomes), glucose 6-phosphatase, polysaccharide phosphorylases a and b, phosphoglucomutase, hexokinase, phosphoglyceromutase, ribonuclease, A-esterase (rabbit serum), cholinesterase (horse serum), chymotrypsin. Alkaline phosphatase and phosphoglucomutase are inhibited by 1mum-beryllium sulphate whereas the other enzymes are largely unaffected by 1mm-beryllium sulphate. 2. Possible mechanisms for the inhibition of phosphoglucomutase and alkaline phosphatase are discussed.
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PMID:The inhibition of enzymes by beryllium. 428 87

It was shown previously in experiments on white rats with alloxan diabetes that trihydroxyoctadecadiene acids from Bryonia alba L. have a hypoglycemic action. The present paper is concerned with the effects of the above-indicated compounds on the activity of glycogen phosphorylase (a- and b-forms), phosphoprotein phosphatase and hexokinase in liver and muscle tissues of white rats with alloxan diabetes. One of the possible mechanisms of the hypoglycemic action of trihydroxyoctadecadiene acids is discussed.
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PMID:[Effect of trihydroxyoctadecadiene acids from Bryonia alba L. on the activity of glycogen metabolism enzymes in alloxan diabetes]. 632 80

Mitochondrially bound brain hexokinase is solubilized by anesthetics and this effect has been suggested to contribute to anesthesia. In the present investigation the influence of the metabolic inhibitor 2-deoxy-D-glucose (2-DOG) was studied. An isolated rat brain preparation was used to avoid the contribution of peripheral reactions. Isolated rat brains were perfused for 45 min with media containing 4 mmol/l glucose, 10 mmol/l 2-DOG and/or 0.4 mmol/l thiopental. The EEG was monitored and acetylcholine, 2-DOG and its 6-phosphate, as well as the intracellular distribution of hexokinase activity were determined in brain tissue. Soluble hexokinase activity in brain cortex was enhanced by 2-DOG, as also by thiopental, and even more pronounced by both drugs used together, Results from in vitro experiments suggest that solubilization of mitochondrial hexokinase after 2-DOG is mediated by intracellularly accumulated 2-DOG-6-phosphate. 2-DOG produced a significant impairment of neuronal activity, revealing EEG patterns similar to those caused by thiopental anesthesia. Cortical acetylcholine levels were elevated by 2-DOG, as well as by thiopental, and again both drugs showed an additive effect when used in combination. This effect which may be the result of an inhibition of acetylcholine release, was also detectable in mice in vivo after 5 g 2-DOG/kg i.p., whereas the same dose of 3-O-methylglucose had no effect. The results provide further evidence that mitochondrial hexokinase may be involved in the relationship between cerebral metabolism and brain function.
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PMID:Relationship between brain mitochondrial hexokinase and neuronal function: comparable effects of 2-deoxy-D-glucose and thiopental. 712 20

The mechanism of action of the antineoplastic drug lonidamine (LND) on MCF-7 human breast cancer cells was studied with the use of 31P and 13C nuclear magnetic resonance (NMR) spectroscopy. The cells were embedded in alginate microcapsules, perfused with growth media and LND at physiological conditions in the NMR tube, and continuously monitored in vivo for the effects of LND. 31P NMR demonstrated intracellular acidification after LND perfusion concomitant with ATP depletion and changes in phospholipid metabolites. 13C NMR showed marked LND-induced accumulation of lactate, and spectra of the perfusate disclosed that LND inhibited lactate transport. Kinetic 13C NMR also furnished information on LND effects on glucose metabolism; LND decreased initial glucose uptake and lactate formation, although the final intracellular glucose levels were higher compared with those in controls. Combined administration of LND and the metabolic inhibitor 2-deoxyglucose yielded additive but not synergistic cytotoxicity and enabled assessment of hexokinase activity. Overall, the results indicate that the major metabolic changes induced by LND are inhibition of lactate transport and its accumulation, which lead to intracellular acidification.
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PMID:Mechanism of action of the antineoplastic drug lonidamine: 31P and 13C nuclear magnetic resonance studies. 779 8

Previous work has indicated that sugar sensing may be important in the regulation of fructan biosynthesis in grasses. We used primary leaves of barley (Hordeum vulgare cv Baraka) to study the mechanisms involved. Excised leaf blades were supplied in the dark with various carbohydrates. Fructan pool sizes and two key enzymes of fructan biosynthesis, sucrose (Suc):Suc-1-fructosyltransferase (1-SST; EC 2. 4.1.99) and Suc:fructan-6-fructosyltransferase (6-SFT; EC 2.4.1.10) were analyzed. Upon supply of Suc, fructan pool sizes increased markedly. Within 24 h, 1-SST activity was stimulated by a factor of three and 6-SFT-activity by a factor of more than 20, compared with control leaves supplemented with mannitol (Mit). At the same time, the level of mRNA encoding 6-SFT increased conspicuously. These effects were increased in the presence of the invertase inhibitor 2, 5-dideoxy-2,5-imino-D-mannitol. Compared with equimolar solutions of Suc, glucose (Glu) and fructose stimulated 6-SFT activity to a lesser extent. Remarkably, trehalose (Tre; Glc-alpha-1 and 1-alpha-Glc) had stimulatory effects on 6-SFT activity and, to a somewhat lesser extent, on 6-SFT mRNA, even in the presence of validoxylamine A, a potent trehalase inhibitor. Tre by itself, however, in the presence or absence of validoxylamine A, did not stimulate fructan accumulation. Monosaccharides phosphorylated by hexokinase but not or weakly metabolized, such as mannose (Man) or 2-deoxy-Glc, had no stimulatory effects on fructan synthesis. When fructose or Man were supplied together with Tre, fructan and starch biosynthesis were strongly stimulated. Concomitantly, phospho-Man isomerase (EC 5.3.1.8) activity was detected. These results indicate that the regulation of fructan synthesis in barley leaves occurs independently of hexokinase and is probably based on the sensing of Suc, and also that the structurally related disaccharide Tre can replace Suc as a regulatory compound.
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PMID:Disaccharide-mediated regulation of sucrose:fructan-6-fructosyltransferase, a key enzyme of fructan synthesis in barley leaves. 1080 43

Tumour cells depend on aerobic glycolysis for adenosine triphosphate (ATP) production, making energy metabolism an interesting therapeutic target. 3-Bromopyruvate (BP) has been shown by others to inhibit hexokinase and eradicate mouse hepatocarcinomas. We report that similar to the glycolysis inhibitor 2-deoxyglucose (DG), BP rapidly decreased cellular ATP within hours, but unlike DG, BP concomitantly induced mitochondrial depolarization without affecting levels of reducing equivalents. Over 24h, and at equitoxic doses, DG reduced glucose consumption more than did BP. The observed BP-induced loss of ATP is therefore largely due to mitochondrial effects. Cell death induced over 24h by BP, but not DG, was blocked by N-acetylcysteine, indicating involvement of reactive oxygen species. BP-induced cytotoxicity was independent of p53. When combined with cisplatin or oxaliplatin, BP led to massive cell death. The anti-proliferative effects of low-dose platinum were strikingly potentiated also in resistant p53-deficient cells. Together with the reported lack of toxicity, this indicates the potential of BP as a clinical chemopotentiating agent.
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PMID:3-Bromopyruvate as inhibitor of tumour cell energy metabolism and chemopotentiator of platinum drugs. 1938 31

Jasmonates act as signal transduction intermediates when plants are subjected to environmental stresses such as UV radiation, osmotic shock and heat. In the past few years several groups have reported that jasmonates exhibit anti-cancer activity in vitro and in vivo and induce growth inhibition in cancer cells, while leaving the non-transformed cells intact. Recently, jasmonates were also discovered to have cytotoxic effects towards metastatic melanoma both in vitro and in vivo. Three mechanisms of action have been proposed to explain this anti-cancer activity. The bio-energetic mechanism - jasmonates induce severe ATP depletion in cancer cells via mitochondrial perturbation. Furthermore, methyl jasmonate (MJ) has the ability to detach hexokinase from the mitochondria. Second, jasmonates induce re-differentiation in human myeloid leukemia cells via mitogen-activated protein kinase (MAPK) activity and were found to act similar to the cytokinin isopentenyladenine (IPA). Third, jasmonates induce apoptosis in lung carcinoma cells via the generation of hydrogen peroxide, and pro-apoptotic proteins of the Bcl-2 family. Combination of MJ with the glycolysis inhibitor 2-deoxy-d-glucose (2DG) and with four conventional chemotherapeutic drugs resulted in super-additive cytotoxic effects on several types of cancer cells. Finally, jasmonates have the ability to induce death in spite of drug-resistance conferred by either p53 mutation or P-glycoprotein (P-gp) over-expression. In summary, the jasmonates are anti-cancer agents that exhibit selective cytotoxicity towards cancer cells, and thus present hope for the development of cancer therapeutics.
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PMID:Methyl jasmonate: a plant stress hormone as an anti-cancer drug. 1966 Jul 69

TNF-related apoptosis-inducing ligand (TRAIL) appears to be a promising anticancer agent as it specifically kills a wide variety of cancer cells. However, resistance of subpopulations of cancer cells to TRAIL-induced cell death remains a major obstacle for successful treatment of cancer using TRAIL-based therapy. In this report we show that the hexokinase inhibitor 2-deoxy-d-glucose (2-DG) efficiently enhances TRAIL-induced apoptosis through downregulation of receptor-interacting protein kinase 1 (RIP1) in breast cancer cells. Although 2-DG alone did not kill breast cancer cells, it sensitized the cells to TRAIL-induced cell death. This could be efficiently inhibited by blockage of the caspase cascade, suggesting 2-DG augments TRAIL-mediated apoptotic signaling. Indeed, treatment with 2-DG resulted in upregulation of TRAIL receptor 2 (TRAIL-R2), downregulation of cIAP1 and XIAP, and reduction in RIP1. The latter appeared to play an important role in regulating sensitivity of breast cancer cells to TRAIL, in that knockdown of RIP1 recapitulated, at least in part, the effect of 2-DG on TRAIL-induced apoptosis. Taken together, these results indicate that 2-DG enhances TRAIL-induced apoptosis in breast cancer cells by multiple mechanisms including suppression of RIP1, and highlight the potential therapeutic benefit of combinations of 2-DG and TRAIL in the treatment of breast cancer.
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PMID:Down-regulation of RIP1 by 2-deoxy-D-glucose sensitizes breast cancer cells to TRAIL-induced apoptosis. 2349 82

Diet has profound effects on animal longevity and manipulation of nutrient sensing pathways is one of the primary interventions capable of lifespan extension. This often is done through caloric restriction (CR) and a variety of CR mimics have been identified that produce life extending effects without adhering to the rigorous CR dietary regimen. Glycerol is a dietary supplement capable mimicking CR by shifting metabolism away from glycolysis and towards oxidative phosphorylation. Glycerol supplementation has a number of beneficial effects, including lifespan extension, improved stress resistance, and enhanced locomotory and mitochondria activity in older age classes. Using rotifers as a model, we show that supplements of 150-300mM glycerol produced 40-50% extension of mean lifespan. This effect was produced by raising glycerol concentration only three times higher than its baseline concentration in rotifer tissues. Glycerol supplementation decreased rotifer reliance on glycolysis and reduced the pro-aging effects of glucose. Glycerol also acted as a chemical chaperone, mitigating damage by protein aggregation. Glycerol treatment improved rotifer swimming performance in older age classes and maintained more mitochondrial activity. Glycerol treatment provided increased resistance to starvation, heat, oxidation, and osmotic stress, but not UV stress. When glycerol was co-administered with the hexokinase inhibitor 2-deoxyglucose, the lifespan extending effect of glycerol was enhanced. Co-administration of glycerol with inhibitors like 2-deoxyglucose can lower their efficacious doses, thereby reducing their toxic side effects.
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PMID:Glycerol extends lifespan of Brachionus manjavacas (Rotifera) and protects against stressors. 2483 91


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