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)

The effect of lonidamine (LND), 1-(2,4-dichlorobenzyl)-1H-indazol-3 carboxylic acid, on the utilization of carbon from 14C-labeled glucose by cell cultures of the permanent strain LI derived from a human glioblastoma multiforme (astrocytoma) has been investigated. The results may be summarized as follows. Aerobic glycolysis is the main energy-yielding process as shown by the fact that the greatest part of glucose carbon atoms is incorporated into lactate. Nevertheless, the amount of glucose converted accounts for only 63% of the lactate produced, indicating the presence of an elevated endogenous aerobic glycolysis. The amount of glucose carbon atoms incorporated into CO2, lipids, nucleic acid, and supporting structures is low. LND decreased the incorporation of 14C activity in all the above mentioned isolated compounds because of its ability to inhibit glucose phosphorylation. Consequently, there is a lower concentration of glucose-6-phosphate which, in turn, affects the rate of formation of several metabolites in glycolytic and pentose phosphate pathways. Experiments with [1-14C]-2-deoxy-D-glucose further substantiate the idea of glucose phosphorylation as a main target of LND and strongly suggest the presence of a mitochondrially bound hexokinase. The higher inhibition of glucose phosphorylation in exponentially growing cells indicates a further shift of the enzyme toward mitochondria-bound form and confirms the importance of the energy status of the cell in eliciting the response to LND. The reduced capacity of LND-treated cells to synthetize ATP and glucose-6-phosphate reflects the decreased synthesis of proteins and nucleic acids, which affects cell growth and duplication.
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PMID:Effect of lonidamine on the utilization of 14C-labeled glucose by human astrocytoma cells. 282 Jul 86

To estimate hemocirculation and proliferating activity of intraventricular tumor, we measured kinetic rate constants (k1, k2, k3) and glucose metabolic rate (kinetic-rCMRGl) using dynamic positron emission tomography (PET), as well as regional cerebral blood flow (rCBF), blood volume (rCBV), oxygen extraction fraction (rOEF), oxygen metabolic rate (rCMRO2) and autoradiographic rCMRGl (arg-rCMRGl), in patients with intraventricular tumor. The subjects included ten patients, five males and five females, aged from 13 to 53 years with a mean age of 32 years old. Eight tumors were located in the lateral ventricle and two extended into the third ventricle through the foramen of Monro. Another two tumors were located in the fourth ventricle. Histological diagnosis was as follows: five cases of central neurocytoma, one subependymal giant cell astrocytoma, one ependymoma, one choroid plexus carcinoma, one subependymoma, and one meningioma. Tumor lesion on the PET images was determined using CT or MRI, which was performed at levels equivalent to those for the PET scans. For quantitative analysis, regions of interest (ROI) on PET images were delineated on the tumor and the contralateral gray matter. Hemocirculation (rCBF, rCBV) of the tumor was similar to or higher than that of the contralateral gray matter, which corresponded to neuroradiological findings of abundant tumor vessels. Oxygen metabolic parameters (rOEF, rCMRO2) were significantly lower than those of the contralateral gray matter. Especially, low rOEF resulted in an excessive blood flow beyond oxygen demand of the tumor. The raised metabolic rate (rCMRO2/rCMRGl), as compared with that of meningiomas or malignant gliomas, suggested aerobic glycolysis. The kinetic rate constants of tracer transport from blood to brain (k1), reverse transport from brain to blood (k2), and phosphorylation (k3) were analyzed according to the three-compartment model of 18F-fluorodeoxyglucose (18FDG). Tumor k1 and k2 values were similar to or higher than those of the contralateral gray matter, suggesting high permeability due to lack of blood-brain barrier and an abundant blood supply. Tumor k3 value, an indicator of hexokinase activity, and kinetic-rCMRGl were lower in six of eight patients. These six patients have been free from tumor recurrence or regrowth, postoperatively. In the other two patients, tumor kinetic-rCMRGl was similar to or higher than that of the contralateral gray matter, suggesting high activity of proliferation. However, one patient received irradiation and has been followed up, and the other received total resection and has shown no recurrence. Functional information concerning intraventricular tumor is obtained by PET analysis, and kinetic analysis of the rate constants is useful for interpreting a detailed metabolic process of glucose, and provides additional information on intraventricular tumor aggressiveness.
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PMID:[Hemocirculation and metabolism in intraventricular tumors: kinetic analysis of glucose metabolism]. 885 49

ATP is released from most cell types and functions as an extracellular signaling molecule through activation of members of the two large families of P2X and P2Y receptors. Although three mammalian P2Y receptors have been cloned that are selectively activated by uridine nucleotides, direct demonstration of the release of cellular UTP has not been reported. Pharmacological studies of the P2Y4 receptor expressed in 1321N1 human astrocytoma cells indicated that this receptor is activated by UTP but not by ATP. Mechanical stimulation of 1321N1 cells also resulted in release of a molecule that markedly activated the expressed P2Y4 receptor. This nucleotide was shown to be UTP by two means. First, high performance liquid chromatography analysis of the medium from [33P]H3PO4-loaded 1321N1 cells illustrated that mechanical stimulation resulted in a large increase in a radioactive species that co-eluted with authentic UTP. This species was degraded by incubation with the nonspecific pyrophosphohydrolase apyrase or with hexokinase and was specifically lost by incubation with the UTP-specific enzyme UDP-glucose pyrophosphorylase. Second, a sensitive assay that quantitates UTP mass at low nanomolar concentrations was devised based on the nucleotide specificity of UDP-glucose pyrophosphorylase. Using this assay, mechanical stimulation of 1321N1 cells was shown to result in an increase of medium UTP levels from 2.6 to 36.4 pmol/10(6) cells within 2 min. This increase was paralleled by a similar augmentation of extracellular ATP levels. A calcein-based fluorescence quenching method was utilized to confirm that none of the increases in medium nucleotide levels could be accounted for by cell lysis. Taken together, these results directly demonstrate the mechanically induced release of UTP and illustrate the efficient coupling of this release to activation of P2Y4 receptors.
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PMID:Direct demonstration of mechanically induced release of cellular UTP and its implication for uridine nucleotide receptor activation. 930 92

Manganese (Mn) is a trace metal required for normal growth and development. Manganese neurotoxicity is rare and usually associated with occupational exposures. However, the cellular and molecular mechanisms underlying Mn toxicity are still elusive. In rats chronically exposed to Mn, their brain regional Mn levels increase in a dose-related manner. Brain Mn preferentially accumulates in mitochondria; this accumulation is further enhanced with Mn treatment in vivo. Exposure of mitochondria to Mn in vitro leads to uncoupling of oxidative phosphorylation. These observations prompted us to investigate the hypothesis that Mn induces alterations in energy metabolism in neural cells by interfering with the activities of various glycolytic and TCA cycle enzymes using human neuroblastoma (SK-N-SH) and astrocytoma (U87) cells. Treatments of SK-N-SH and U87 cells with MnCl2 induced cell death in these cells, in a concentration- and time-dependent manner, as determined by MTT assays. In parallel with the Mn-induced, dose-dependent decrease in cell survival, treatment of these cells with 0.01 to 4.0 mM MnCl2 for 48 h also induced dose-related decreases in their activities of hexokinase, pyruvate kinase, lactate dehydrogenase, citrate synthase, and malate dehydrogenase. Hexokinase in SK-N-SH cells was the most affected by Mn treatments, even at the lower range of concentrations. Mn treatment of SK-N-SH cells affected pyruvate kinase and citrate synthase to a lesser extent as compared to its effect on other enzymes investigated. However, citrate synthase and pyruvate kinase in U87 cells were more vulnerable than other enzymes investigated to the effects of Mn. The results suggest the two cell types exhibited differential susceptibility toward the Mn-induced effects. Additionally, the results may have significant implications in flux control because HK is the first and highly regulated enzyme in brain glycolysis. Thus these results are consistent with our hypothesis and may have pathophysiological implications in the mechanisms underlying Mn neurotoxicity.
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PMID:Differential lowering by manganese treatment of activities of glycolytic and tricarboxylic acid (TCA) cycle enzymes investigated in neuroblastoma and astrocytoma cells is associated with manganese-induced cell death. 1509 32

Enzyme activity changes in reagent and neoplastic glia are examined. In the case of reagent glia, considerably increased ADPase, ATPase and AMPase values have been observed in experimental elective parenchymal necrosis in the rat, in hypertrophic astrocytes from recent plaques in multiple necrosis, in demyelinisation associated with cyanide encephalopathy, and in reagent astrocytes surrounding tumours and arteriosclerosis sites. Depressed ATPase values have been observed in experimental oedema, as compared with increased TPPase in human oedema. BuChE and ChE activity disappears in both oligodendro- and astroglia near old cerebral infarct sites, whereas there is marked BuChE activity peripherally to multiple sclerosis plaques and in areas of phenylpyruvic oligophrenia demyelinisation. In neoplastic glia, ADPase is clearly evident in malignant gliomas, ATPase is related to the extent of the cell body, AMPase is positive in medulloblastoma cell cytoplasm and beta-glucuronidase increases in anaplasia. Above-normal ChE activity has been observed in astrocyte tumors, while BuChE is greater than that of AChE. Phosphorylase reaction is intense in astrocytoma and in glioblastoma giant cells. Phosphoglucomutase values are below-normal in tumours, except in the case of ependymoma, while both phosphohexoisomerase and hexokinase display increased activity in atypical forms.
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PMID:[Histochemical demonstration of glial enzyme activity. II. Reagent and neoplastic glia]. 1734 Aug 8