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)

We investigated the effect of maternal nicotine exposure during pregnancy and lactation on carbohydrate metabolism in the neonatal lung. Female rats received nicotine (1 mg/kg body weight/day) subcutaneously from day 7 after mating. Control animals received saline. The suckling rats were killed 24 hours after the last dose of nicotine was administered to the mother on postnatal day 14. The lung tissue of 9 rat pups from 3 litters was surgically removed and the in vitro utilization of exogenous glucose (micromol/g wet lung tissue/h) was determined. Lactate production (micromol/g wet lung tissue/h) was also determined to assess glycolytic activity. Maternal nicotine exposure during pregnancy and lactation stimulated glucose turnover by 21.6% (P<.01), but suppressed glycolysis by 24.6% (P<.001) and glycogenolysis by 37.9% (P<.001). Maternal nicotine exposure during gestation and lactation had no effect on the activity of hexokinase (U/g wet lung tissue), but resulted in a lower phosphofructokinase activity (U/g wet lung tissue) in the lungs of the offspring. From the data, it appeared that the inhibition of the flux of glucose through the glycolytic pathway can be attributed to an inhibition of phosphofructokinase.
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PMID:Maternal nicotine exposure during pregnancy and lactation: I. Effect on glycolysis in the lungs of the offspring. 1255 55

1. Sheep-, rabbit- and ox-muscle minces prepared soon after slaughter were diluted with 1 vol. of 0.16 m-potassium chloride in the absence (potassium chloride mince) and presence of added cofactor or glycolysable substrate, and the effects on the ultimate pH were examined. 2. Changes in the concentrations of glycogen and lactate and the concentrations of some phosphorus-containing fractions were determined in ox-muscle preparations. 3. Glycolysis ceased at appreciably higher pH in the potassium chloride mince than in undiluted mince. The inclusion of glycogen, ATP, ADP, NAD or magnesium chloride in the diluent had little effect on the ultimate pH of the diluted mince. 4. Lactic acid production continued at lower pH values in diluted mince containing added glucose 1-phosphate, fructose 1,6-diphosphate or glucose plus hexokinase than in potassium chloride mince. 5. The evidence points to failure of the phosphorylase step being responsible for the dilution effect.
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PMID:Post-mortem glycolysis in skeletal muscle. The extent of glycolysis in diluted preparation of mammalian muscle. 1674 88

Clenbuterol, a beta2-adrenergic-receptor agonist, is known to provoke muscle hypertrophy and a slow-to-fast phenotype change. A more glycolytic phenotype should be paralleled by changes in muscle glycolytic metabolism. Two groups (n=16 for each) of 3-month-old male Wistar rats (UCL: untrained clenbuterol, and ECL: exercised clenbuterol) received a chronic administration of clenbuterol (2 mg/kg body weight/day). Two other groups of animals (U: untrained and E: exercised), were given a 0.9% NaCl solution instead of clenbuterol. E and ECL animals followed an 8-week progressive isometric force strength-training program. Both clenbuterol administration and training resulted in an increase in extensor digitorum longus (EDL) mass despite the fact that this muscle was indirectly mobilised during isometric force strength training. Clenbuterol and training induced a consistent slow-to-fast phenotype change without drastically increasing specific activities of glycolytic enzymes. Except for GAPDH and hexokinase, modifications in glycolytic-enzyme-specific activities were not explained by transcriptional changes. Lactate dehydrogenase activity was not affected by clenbuterol but was strongly augmented by training. In EDL of ECL rats, both treatments presented an opposite effect compensating each other. GLUT1 mRNA expression was augmented in EDL of UCL and ECL animals, whereas monocarboxylate transporter 1 mRNA amounts were decreased in EDL of UCL rats. Citrate synthase activity was reduced by clenbuterol treatment but remained unchanged in EDL of E animals. Creatine kinase activity was enhanced only by clenbuterol alone. These data show that clenbuterol-induced muscle hypertrophy and slow-to-fast phenotype changes are not associated with a glycolytic-enzyme-activity increase. They also suggest that in EDL isometric force strength training can reverse clenbuterol-induced molecular adaptations.
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PMID:Molecular impact of clenbuterol and isometric strength training on rat EDL muscles. 1709 70

Decoding of the bioenergetic signature underlying embryonic stem cell cardiac differentiation has revealed a mandatory transformation of the metabolic infrastructure with prominent mitochondrial network expansion and a distinctive switch from glycolysis to oxidative phosphorylation. Here, we demonstrate that despite reduction in total glycolytic capacity, stem cell cardiogenesis engages a significant transcriptome, proteome, as well as enzymatic and topological rearrangement in the proximal, medial, and distal modules of the glycolytic pathway. Glycolytic restructuring was manifested by a shift in hexokinase (Hk) isoforms from Hk-2 to cardiac Hk-1, with intracellular and intermyofibrillar localization mapping mitochondrial network arrangement. Moreover, upregulation of cardiac-specific enolase 3, phosphofructokinase, and phosphoglucomutase and a marked increase in glyceraldehyde 3-phosphate dehydrogenase (GAPDH) phosphotransfer activity, along with apparent post-translational modifications of GAPDH and phosphoglycerate kinase, were all distinctive for derived cardiomyocytes compared to the embryonic stem cell source. Lactate dehydrogenase (LDH) isoforms evolved towards LDH-2 and LDH-3, containing higher proportions of heart-specific subunits, and pyruvate dehydrogenase isoforms rearranged between E1alpha and E1beta, transitions favorable for substrate oxidation in mitochondria. Concomitantly, transcript levels of fetal pyruvate kinase isoform M2, aldolase 3, and transketolase, which shunt the glycolytic with pentose phosphate pathways, were reduced. Collectively, changes in glycolytic pathway modules indicate active redeployment, which would facilitate connectivity of the expanding mitochondrial network with ATP utilization sites. Thus, the delineated developmental dynamics of the glycolytic phosphotransfer network is integral to the remodeling of cellular energetic infrastructure underlying stem cell cardiogenesis.
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PMID:Glycolytic network restructuring integral to the energetics of embryonic stem cell cardiac differentiation. 2004 4

Pulmonary microvascular endothelial cells possess both highly proliferative and angiogenic capacities, yet it is unclear how these cells sustain the metabolic requirements essential for such growth. Rapidly proliferating cells rely on aerobic glycolysis to sustain growth, which is characterized by glucose consumption, glucose fermentation to lactate, and lactic acidosis, all in the presence of sufficient oxygen concentrations. Lactate dehydrogenase A converts pyruvate to lactate necessary to sustain rapid flux through glycolysis. We therefore tested the hypothesis that pulmonary microvascular endothelial cells express lactate dehydrogenase A necessary to utilize aerobic glycolysis and support their growth. Pulmonary microvascular endothelial cell (PMVEC) growth curves were conducted over a 7-day period. PMVECs consumed glucose, converted glucose into lactate, and acidified the media. Restricting extracellular glucose abolished the lactic acidosis and reduced PMVEC growth, as did replacing glucose with galactose. In contrast, slow-growing pulmonary artery endothelial cells (PAECs) minimally consumed glucose and did not develop a lactic acidosis throughout the growth curve. Oxygen consumption was twofold higher in PAECs than in PMVECs, yet total cellular ATP concentrations were twofold higher in PMVECs. Glucose transporter 1, hexokinase-2, and lactate dehydrogenase A were all upregulated in PMVECs compared with their macrovascular counterparts. Inhibiting lactate dehydrogenase A activity and expression prevented lactic acidosis and reduced PMVEC growth. Thus PMVECs utilize aerobic glycolysis to sustain their rapid growth rates, which is dependent on lactate dehydrogenase A.
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PMID:Critical role for lactate dehydrogenase A in aerobic glycolysis that sustains pulmonary microvascular endothelial cell proliferation. 2067 37

The present study was designed to analyze the effect of acute aluminium phosphide (ALP) (10 mg/kg body wt.) exposure on the glucose homeostasis in rat liver and brain. ALP has been implicated in the inhibition of cytochrome oxidase causing reduced oxygen uptake and decreased ATP synthesis eventually resulting in cellular energy crisis. A significant decrease in plasma glucose levels in the ALP treated rats has been observed. Therefore, decreased ATP levels coupled with hypoglycemia may further intensify the cellular energy deficits. In order to meet the sudden increase in the local energy demand, the brain tissue utilizes its stored energy in the form of glycogen breakdown as observed by a decrease in the glycogen levels in both liver and brain which was accompanied by a marked increase in the activity of glycogen phosphorylase in both the tissues. The glycolytic rate was found to be enhanced in brain tissue as evident by increased activities of hexokinase and phosphofructokinase enzymes, but decreased in liver of ALP treated rats. Lactate levels were increased in plasma and brain, but decreased in liver of ALP treated rats. Pyruvate levels increased in the plasma and liver, but no change was observed in the brain tissue. ALP did not cause any change in the gluconeogenic enzymes like glucose-6-phosphatase and fructose-1,6-bisphophatase in brain, but a significant increase was observed in the liver. Results of the study showed that ALP induced cellular energy deficit leads to compromised energy status of liver and brain coupled with substantial alterations in glucose homeostasis. However, the activity of glucose-6-phosphate dehydrogenase decreased significantly in both the tissues.
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PMID:Altered glucose homeostasis in response to aluminium phosphide induced cellular oxygen deficit in rat. 2092 55

We examined the effects of lactate on the enzymatic activity of hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK) in various mouse tissues. Our results showed that lactate inhibited PFK activity in all the analyzed tissues. This inhibitory effect was observed in skeletal muscle even in the presence of insulin. Lactate directly inhibited the phosphorylation of PFK tyrosine residues in skeletal muscle, an important mechanism of the enzyme activation. Moreover, lactate indirectly inhibited HK activity, which resulted from its cellular redistribution, here attributed to alterations of HK structure. PK activity was not affected by lactate. The activity of HK and PFK is directly related to glucose metabolism. Thus, it is conceivable that lactate exposure can induce inhibition of glucose consumption in tissues.
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PMID:Lactate downregulates the glycolytic enzymes hexokinase and phosphofructokinase in diverse tissues from mice. 2107 28

Cetuximab, an anti-HER1 (EGFR) antibody, is currently under trial for the treatment of breast cancer. HER1 expression is not necessarily a predictor of response to cetuximab as mutant components of the pathways activated by HER1 which include PI3K/Akt can lead to resistance. Techniques that monitor events downstream of HER1 are more likely to provide an accurate measure of the efficacy of an anti-HER1 treatment. Glucose metabolism has been shown to be strongly influenced by the state of activation of PI3K/Akt. Here, the association between [18F]-FDG incorporation in breast cancer cells during response to cetuximab is investigated. The study also reviews the development of medical imaging probes that target HER1 The sensitivity to cetuximab of three breast tumour cell lines, SKBr3, MDA-MB-453 and MDA-MB-468, expressing HER1 at low and high levels, are determined using an MTT assay over a six-day period and a clonogenic assay carried out after seven- and 10-day exposures. Incorporation of FDG by cells treated with growth inhibitory doses of cetuximab were carried out after 4 hand two, four and six days of treatment. Glucose transport (rate of uptake of the non-metabolisable analogue [3H]o-methyl-D-glucose), hexokinase activity and lactate production were measured on cells treated with inhibitory doses of cetuximab for six days. The IC50, dose for MDA-MB-468 cells and the IC10 (maximum achievable inhibition) doses for MDA-MB-543 and SKBr3 treated with cetuximab for six days were 2.6, 5 and 148 microg/mL, respectively. Incorporation of FDG by SKBr3 and MDA-MB-453 cells was found to be decreased by MDA-MB468 cells using IC50, and IC20, doses of cetuximab for six days. Lactate production was found to be increased by MDA-MB-468 cells responding to cetuximab. Incorporation of FDG at the tumour cell level is modulated by treatment with growth inhibitory doses of cetuximab in cells sensitive to cetuximab due to modulation of HK activity.
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PMID:Predicting tumour response to anti-HER1 therapy using medical imaging: a literature review and in vitro study of [18F]-FDG incorporation by breast cancer cells responding to cetuximab. 2195 Feb 9

The study was aimed at assessing the total enzyme activity and the profile of breast cancer and dysplasia on the human material. In addition, the validity of data was evaluated from the aspect of improving diagnostics. Lactate dehydrogenase activity, as well as the profile of its isoenzymes, pyruvate kinase and hexokinase, were measured. The study included 60 samples of breast cancer, out of which 20 were benign breast tumours and 40 were 1st and 2nd degree dysplasia of the breast. The samples were collected from the patients operated at the Institute for Oncology of Faculty of Medicine in Sremska Kamenica. Lactate dehydrogenase isoenzymes were separated by the vertical polyacrylamide gel disc electrophoresis according to the slightly modified Brewer and Ashworth's method. The activity of all the tested enzymes was measured under the conditions of linear kinetics in the function of time and enzyme concentration. Lactate dehydrogenase-5 was found in 88% of the analyzed breast cancer samples, whereas it was not detected in breast dysplasia. Pyruvate kinase (4.-isoenzyme) was about 50 times higher and the activity of hexokinase was 3 times higher in breast cancer than in breast dysplasia. Lactate dehydrogenase-5 and pyruvate kinase (4.-isoenzyme) are particularly important and reliable markers of malignity. The results obtained for quantitative and qualitative changes in the enzyme activity can be used to improve diagnostics and early diagnostics of malignant breast neoplasm.
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PMID:Comparison of glycolytic enzyme and isoenzyme activity in breast cancers and dysplasia. 2273 Jul 3

We previously demonstrated that mitochondrial bioenergetic deficits in the female brain accompanied reproductive senescence and was accompanied by a shift from an aerobic glycolytic to a ketogenic phenotype. Herein, we investigated the relationship between systems of fuel supply, transport and mitochondrial metabolic enzyme expression/activity during aging (3-15 months) in the hippocampus of nontransgenic (nonTg) background and 3xTgAD female mice. Results indicate that during female brain aging, both nonTg and 3xTgAD brains undergo significant decline in glucose transport, as detected by FDG-microPET, between 6-9 months of age just prior to the transition into reproductive senescence. The deficit in brain metabolism was sustained thereafter. Decline in glucose transport coincided with significant decline in neuronal glucose transporter expression and hexokinase activity with a concomitant rise in phosphorylated/inactivated pyruvate dehydrogenase. Lactate utilization declined in parallel to the decline in glucose transport suggesting lactate did not serve as an alternative fuel. An adaptive response in the nonTg hippocampus was a shift to transport and utilization of ketone bodies as an alternative fuel. In the 3xTgAD brain, utilization of ketone bodies as an alternative fuel was evident at the earliest age investigated and declined thereafter. The 3xTgAD adaptive response was to substantially increase monocarboxylate transporters in neurons while decreasing their expression at the BBB and in astrocytes. Collectively, these data indicate that the earliest change in the metabolic system of the aging female brain is the decline in neuronal glucose transport and metabolism followed by decline in mitochondrial function. The adaptive shift to the ketogenic system as an alternative fuel coincided with decline in mitochondrial function. Translationally, these data provide insights into the earliest events in bioenergetic aging of the female brain and provide potential targets for preventing shifts to less efficient bioenergetic fuels and transition to the ketogenic phenotype of the Alzheimer's brain.
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PMID:Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention. 2424 84


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