Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.1.1 (hexokinase)
5,274 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exercise induces a rapid increase in expression of the GLUT4 isoform of the glucose transporter in skeletal muscle. One of the signals responsible for this adaptation appears to be an increase in cytosolic Ca(2+). Myocyte enhancer factor 2A (MEF2A) is a transcription factor that is involved in the regulation of GLUT4 expression. It has been reported that the Ca(2+)-regulated phosphatase calcineurin mediates the activation of MEF2 by exercise. It has also been shown that the expression of activated calcineurin in mouse skeletal muscle results in an increase in GLUT4. These findings suggest that increases in cytosolic Ca(2+) induce increased GLUT4 expression by activating calcineurin. However, we have obtained evidence that this response is mediated by a Ca(2+)-calmodulin-dependent protein kinase. The purpose of this study was to test the hypothesis that calcineurin is involved in mediating exercise-induced increases in GLUT4. Rats were exercised on 5 successive days using a swimming protocol. One group of swimmers was given 20 mg/kg body weight of cyclosporin, a calcineurin inhibitor, 2 h before exercise. A second group was given vehicle. GLUT4 protein was increased approximately 80%, GLUT4 mRNA was increased approximately 2.5-fold, MEF2A protein was increased twofold, and hexokinase II protein was increased approximately 2.5-fold 18 h after the last exercise bout. The cyclosporin treatment completely inhibited calcineurin activity but did not affect the adaptive increases in GLUT4, MEF2A, or hexokinase expression. We conclude that calcineurin activation does not mediate the adaptive increase in GLUT4 expression induced in skeletal muscle by exercise.
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PMID:Calcineurin does not mediate exercise-induced increase in muscle GLUT4. 1573 36

1. The present study was designed to examine the role of calcineurin in muscle metabolic components by the administration of the specific calcineurin inhibitor cyclosporine A (CsA) to rats. 2. Male Wistar rats were divided into either a CsA-treated group (CT) or a vehicle-treated group (VT). Cyclosporine A was administered subcutaneously to rats at a rate of 25 mg/kg bodyweight per day for 10 successive days. Thereafter, changes in muscle enzyme activities and glucose transporter (GLUT)-4 and monocarboxylate transporter (MCT)-1 and MCT-4 proteins in the slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles were examined. 3. There was a significant increase in MCT-1 and MCT-4 proteins in the soleus muscle in the CT group, but not in the EDL muscle. The activities of hexokinase, pyruvate kinase and lactate dehydrogenase in the soleus muscle also increased significantly in the CT group, but a similar increase in enzyme activity was not seen in EDL muscle. The activities of citrate synthase or malate dehydrogenase and the GLUT-4 protein content were not altered by CsA treatment in either the soleus or EDL muscles. 4. These results seem to imply that calcineurin negatively regulates the components of glucose/lactate metabolism, except for GLUT-4, especially in slow-twitch muscle.
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PMID:Inhibition of calcineurin increases monocarboxylate transporters 1 and 4 protein and glycolytic enzyme activities in rat soleus muscle. 1574 6

Several drug-resistant mammalian cell types exhibit increased glycolytic rates, preferential synthesis of ATP through oxidative phosphorylation, and altered glucose transport. Herein we analyzed the influence of parasite growth phase on energy substrate uptake and use in a Leishmania strain [NR(Gr)] selected for resistance against glibenclamide. Glibenclamide is an ABC-transporter blocker which modulates the function of glucose transporters in some mammalian cells. Our results demonstrate for the first time that compared to glibenclamide-sensitive Leishmania, exponential phase glibenclamide-resistant parasites exhibit decreased use of glucose as energy substrate, decreased glucose uptake and decreased glucose transporter expression. However, compared to glibenclamide-sensitive cells, stationary phase resistant parasites display an increased use of amino acids as energy substrate and an increased activity of the enzymes hexokinase, phosphoglucose isomerase, and especially NAD(+)-linked glutamate dehydrogenase. These results suggest that drug resistance in Leishmania involves a metabolic adaptation that promotes a stage dependent modulation of energy substrate uptake and use as a physiological response to the challenge imposed by drug pressure.
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PMID:Substrate preferences and glucose uptake in glibenclamide-resistant Leishmania parasites. 1588 61

A mathematical model of glycolysis in bloodstream form Trypanosoma brucei was developed previously on the basis of all available enzyme kinetic data (Bakker, B. M., Michels, P. A. M., Opperdoes, F. R., and Westerhoff, H. V. (1997) J. Biol. Chem. 272, 3207-3215). The model predicted correctly the fluxes and cellular metabolite concentrations as measured in non-growing trypanosomes and the major contribution to the flux control exerted by the plasma membrane glucose transporter. Surprisingly, a large overcapacity was predicted for hexokinase (HXK), phosphofructokinase (PFK), and pyruvate kinase (PYK). Here, we present our further analysis of the control of glycolytic flux in bloodstream form T. brucei. First, the model was optimized and extended with recent information about the kinetics of enzymes and their activities as measured in lysates of in vitro cultured growing trypanosomes. Second, the concentrations of five glycolytic enzymes (HXK, PFK, phosphoglycerate mutase, enolase, and PYK) in trypanosomes were changed by RNA interference. The effects of the knockdown of these enzymes on the growth, activities, and levels of various enzymes and glycolytic flux were studied and compared with model predictions. Data thus obtained support the conclusion from the in silico analysis that HXK, PFK, and PYK are in excess, albeit less than predicted. Interestingly, depletion of PFK and enolase had an effect on the activity (but not, or to a lesser extent, expression) of some other glycolytic enzymes. Enzymes located both in the glycosomes (the peroxisome-like organelles harboring the first seven enzymes of the glycolytic pathway of trypanosomes) and in the cytosol were affected. These data suggest the existence of novel regulatory mechanisms operating in trypanosome glycolysis.
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PMID:Experimental and in silico analyses of glycolytic flux control in bloodstream form Trypanosoma brucei. 1595 17

Using human (SK-MEL 23, SK-MEL 24 and G361) and murine (B16) melanoma cell lines, the coregulatory potential of the uptake of the positron emission tomography (PET) tracer, [Fluorine-18] 2-fluoro-2-deoxy-D-glucose (F-18 FDG) has been investigated in relationship to tumor characteristics. Comparative studies among the four melanoma cell lines demonstrated that the lowest FDG uptake in SK-MEL 24 corresponded strongly to the data for DT (population doubling time) and MTT (tetrazolium salt) cell viability as well as hexokinase (HK) activity, but was not related to the glucose transporter 1 (GLUT 1) expression level. Furthermore, the FDG uptake in each melanoma cell line measured by cell cycle kinetics was significantly positively correlated to both the proliferation index (PI=S/G2M phase fractions) and the cell viability, though with one exception relating to the PI of the lowest FDG uptake cell line, SK-MEL 24. No positive correlation was found between the expression of GLUT 1 and FDG uptake in any individual cell line. However, the HK activities in SK-MEL 23 and 24 showed considerable positive relationships with FDG uptake. Our present study suggests that both the proliferation rate and the cell viability of melanoma cells may be key factors for FDG uptake and that HK activity, rather than GLUT 1 expression, seems to be a major factor.
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PMID:Factors influencing [F-18] 2-fluoro-2-deoxy-D-glucose (F-18 FDG) uptake in melanoma cells: the role of proliferation rate, viability, glucose transporter expression and hexokinase activity. 1604 94

Ovarian follicle development in egg-laying species is characterized by rapid growth in 7 days prior to ovulation when DNA and protein synthesis is markedly increased in the granulosa and theca cells. However, energy and substrate sources to facilitate the extensive DNA and protein synthesis necessary for folliculogenesis have not been identified in avian species. The current study was undertaken to investigate the expression profiles of regulatory genes involved in glucose transport, glycolysis and fatty acid oxidation in the follicle membranes from the small white follicle (SWF) to follicle 1 (F1) stages of follicle development. In our analysis of glucose transporter (GLUT) isoform expression, the level of GLUT1 mRNA increased with follicle development while GLUT2, GLUT3 and GLUT8 mRNA levels were unaffected by follicle development. In contrast, the expression patterns of proteins involved in metabolism down-stream of glucose transport, including hexokinase (HK), pyruvate dehydrogenase E1alpha (PDH E1alpha) and citrate synthase (CS), did not vary with the developmental stage of the follicle, even during rapid follicle growth. Expression of genes related to beta-oxidation of fatty acids (carnitine palmityl CoA transferase I and II, l-3-hydroxyacyl CoA dehydrogenase and long-chain acyl-CoA dehydrogenase), for which expression in the ovarian follicles of mammalian species has not previously been studied, was not changed consistently with the follicle development. These results suggest that both glucose and fatty acids might work as energy sources to ensure rapid follicle development in the chicken ovary, even though glycolysis and beta-oxidation are not modulated by follicle development.
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PMID:Changes in gene expression involved in energy utilization during chicken follicle development. 1625 45

The phosphatidylinositol 3-kinase (PI3K) signal transduction pathway is a well known mediator of cell growth, proliferation, and survival signals. Whereas the expression and function of this pathway has been documented during mammalian development, evidence demonstrating the physiologic importance of this pathway in murine preimplantation embryos is beginning to emerge. This study demonstrates that inhibition of the PI3K pathway leads to the induction of apoptosis in both murine blastocysts and trophoblast stem cells. The apoptosis induced in both model systems correlates with a decrease in the expression of the glucose transporter GLUT1 at the plasma membrane. In addition, blastocysts cultured in the presence of the PI3K inhibitor LY-294002 display a decrease in both 2-deoxyglucose uptake and hexokinase activity as compared with control blastocysts. To determine the impact of PI3K inhibition on pregnancy outcome, embryo transfer experiments were performed. Blastocysts cultured in the presence of LY-294002 demonstrate a dramatic increase in fetal resorptions as compared with control embryos. Finally, we demonstrate that impairment of glucose metabolism via iodoacetate, a glyceraldehyde-3-phosphate dehydrogenase inhibitor, is sufficient to induce apoptosis in both blastocysts and trophoblast stem cells. Moreover, blastocysts treated with iodoacetate result in poor pregnancy outcome as determined by embryo transfer experiments. Taken together these data demonstrate the critical importance of the PI3K pathway in preimplantation embryo survival and pregnancy outcome and further emphasize the importance of glucose utilization and metabolism in cell survival pathways.
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PMID:Phosphatidylinositol 3-kinase activity is critical for glucose metabolism and embryo survival in murine blastocysts. 1627 57

A nonradioisotope, 96-well-microplate assay to evaluate glucose uptake activity in cultured cells has been developed. 2-Deoxyglucose (2DG) was detected by measuring a potent fluorophore, resorufin, generated after incubation with a single assay solution containing hexokinase, adenosine 5'-triphosphate, glucose 6-phosphate dehydrogenase, beta-nicotineamide adenine dinucleotide phosphate, diaphorase, and resazurin. This amplifying detection system could detect the fluorescence intensity induced by uptake of 2DG into L6 skeletal muscle cells, even at the level of cells cultivated in individual wells in a 96-well microplate. Using this assay system, the effects of insulin, cytochalasin B (hexose uptake inhibitor), LY294002 (inhibitor of glucose transporter translocation), and pioglitazone hydrochloride (insulin-sensitizing agent) on 2DG uptake into L6 myotubes could be assessed clearly. Therefore, our simple method may be useful for in vitro high-throughput screening and for evaluating regulators of glucose uptake.
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PMID:A nonradioisotope, enzymatic assay for 2-deoxyglucose uptake in L6 skeletal muscle cells cultured in a 96-well microplate. 1644 89

Control analysis of the glycolytic flux was carried out in two fast-growth tumor cell types of human and rodent origin (HeLa and AS-30D, respectively). Determination of the maximal velocity (V(max)) of the 10 glycolytic enzymes from hexokinase to lactate dehydrogenase revealed that hexokinase (153-306 times) and phosphofructokinase-1 (PFK-1) (22-56 times) had higher over-expression in rat AS-30D hepatoma cells than in normal freshly isolated rat hepatocytes. Moreover, the steady-state concentrations of the glycolytic metabolites, particularly those of the products of hexokinase and PFK-1, were increased compared with hepatocytes. In HeLa cells, V(max) values and metabolite concentrations for the 10 glycolytic enzyme were also significantly increased, but to a much lesser extent (6-9 times for both hexokinase and PFK-1). Elasticity-based analysis of the glycolytic flux in AS-30D cells showed that the block of enzymes producing Fru(1,6)P2 (i.e. glucose transporter, hexokinase, hexosephosphate isomerase, PFK-1, and the Glc6P branches) exerted most of the flux control (70-75%), whereas the consuming block (from aldolase to lactate dehydrogenase) exhibited the remaining control. The Glc6P-producing block (glucose transporter and hexokinase) also showed high flux control (70%), which indicated low flux control by PFK-1. Kinetic analysis of PFK-1 showed low sensitivity towards its allosteric inhibitors citrate and ATP, at physiological concentrations of the activator Fru(2,6)P2. On the other hand, hexokinase activity was strongly inhibited by high, but physiological, concentrations of Glc6P. Therefore, the enhanced glycolytic flux in fast-growth tumor cells was still controlled by an over-produced, but Glc6P-inhibited hexokinase.
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PMID:Determining and understanding the control of glycolysis in fast-growth tumor cells. Flux control by an over-expressed but strongly product-inhibited hexokinase. 1664 May 61

A key hallmark of many cancers, particularly the most aggressive, is the capacity to metabolize glucose at an elevated rate, a phenotype detected clinically using positron emission tomography (PET). This phenotype provides cancer cells, including those that participate in metastasis, a distinct competitive edge over normal cells. Specifically, after rapid entry of glucose into cancer cells on the glucose transporter, the highly glycolytic phenotype is supported by hexokinase (primarily HK II) that is overexpressed and bound to the outer mitochondrial membrane via the porin-like protein voltage-dependent anion channel (VDAC). This protein and the adenine nucleotide transporter move ATP, newly synthesized by the inner membrane located ATP synthase, to active sites on HK II. The abundant amounts of HK II bind both the ATP and the incoming glucose producing the product glucose-6-phosphate, also at an elevated rate. This critical metabolite then serves both as a biosynthetic precursor to support cell proliferation and as a precursor for lactic acid, the latter exiting cancer cells causing an unfavorable environment for normal cells. Although helping facilitate this chemical warfare, HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host. For these reasons, targeting this key enzyme is currently being investigated in several laboratories in a strategy to develop novel therapies that may turn the tide on the continuing struggle to find effective cures for cancer. One such candidate is 3-bromopyruvate that has been shown recently to eradicate advanced stage, PET positive hepatocellular carcinomas in an animal model without apparent harm to the animals.
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PMID:Hexokinase II: cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. 1689 90


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