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)

Glucose and glutamine metabolism in several cultured mammalian cell lines (BHK, CHO, and hybridoma cell lines) were investigated by correlating specific utilization and formation rates with specific maximum activities of regulatory enzymes involved in glycolysis and glutaminolysis. Results were compared with data from two insect cell lines and primary liver cells. Flux distribution was measured in a representative mammalian (BHK) and an insect (Spodoptera frugiperda) cell line using radioactive substrates. A high degree of similarity in many aspects of glucose and glutamine metabolism was observed among the cultured mammalian cell lines examined. Specific glucose utilization rates were always close to specific hexokinase activities, indicating that formation of glucose-6-phosphate from glucose (catalyzed by hexokinase) is the rate limiting step of glycolysis. No activity of the key enzymes connecting glycolysis with the tricarboxylic acid cycle, such as pyruvate dehydrogenase, pyruvate carboxylase, and phosphoenolpyruvate carboxykinase, could be detected. Flux distribution in BHK cells showed glycolytic rates very similar to lactate formation rates. No glucose- or pyruvate-derived carbon entered the tricarboxylic acid cycle, indicating that glucose is mainly metabolized via glycolysis and lactate formation. About 8% of utilized glucose was metabolized via the pentose phosphate shunt, while 20 to 30% of utilized glucose followed pathways other than glycolysis, the tricarboxylic acid cycle, or the pentose phosphate shunt. About 18% of utilized glutamine was oxidized, consistent with the notion that glutamine is the major energy source for mammalian cell lines. Mammalian cells cultured in serum-free low-protein medium showed higher utilization rates, flux rates, and enzyme activities than the same cells cultured in serum-supplemented medium. Insect cells oxidized glucose and pyruvate in addition to glutamine. Furthermore, insect cells produced little or no lactate and were able to channel glycolytic intermediates into the tricarboxylic acid cycle. Metabolic profiles of the type presented here for a variety of cell lines may eventually enable one to interfere with the metabolic patterns of cells relevant to biotechnology, with the hope of improving growth rate and/or productivity.
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PMID:Comparative analysis of glucose and glutamine metabolism in transformed mammalian cell lines, insect and primary liver cells. 855 65

Glycogen content as well as glycolytic, gluconeogenic and fatty acid synthesis enzyme activities were monitored in young and adult male rats fed diets differing in fat content: 11% (low), 22% (medium) and 42% (high) of total energy from fat. The results showed significant differences in the responses of young and adult rats to changes in dietary fat and carbohydrate. In young animals, increasing dietary fat decreased total liver glycogen phosphorylase (GP), pyruvate kinase (PK), glycerol 3-phosphate dehydrogenase, glucose 6-phosphate dehydrogenase, malic enzyme (ME), ATP-citrate lyase (ATP-CL) and fatty acid synthase (FAS). Increasing dietary fat also affected enzyme levels in other tissues: hexokinase (HK) and pyruvate dehydrogenase (PDH) activities decreased whereas skeletal muscle PK activity increased. The pattern of enzyme changes was similar in livers of fed adults with the exception that liver GP was not affected by dietary manipulations. Overnight food deprivation decreased liver glucokinase (GK), ME, ATP-CL, and FAS activities and increased liver phosphoenolpyruvate carboxykinase (PEPCK) and phosphofructokinase in both young and adult animals. In young animals, food deprivation also: (i) reduced liver GK and PK, (ii) increased kidney PEPCK, (iii) decreased muscle PEPCK and (iv) decreased kidney PDH. Food-deprived adults had increased skeletal muscle PEPCK and kidney glycogen synthetase as well as decreased kidney PEPCK muscle GP activity. These differences suggest that young animals are somewhat more responsive to changes in dietary manipulations. They also show that overnight food restriction causes a more profound metabolic re-organization in younger than in older animals.
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PMID:Enzymes of carbohydrate metabolism in young and adult rats fed diets differing in fat and carbohydrate. 881 10

The steady-state levels of messenger RNA (mRNA) of the glucose transporters 1 and 3 and the glycolytic enzymes hexokinase, phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase and pyruvate dehydrogenase were measured in up to seven brain regions of the rat in a recently developed animal model of 'behavioral dependence' on ethanol. Irreversible behavioral dependence, including loss of control, was induced by offering the rats the choice between ethanol and water over a 9-month period (Group A). This group was compared with a group given the choice between ethanol and water for only 2 months (not yet behaviorally dependent, Group B), a group forced to consume ethanol as sole fluid over a 9-month period (not behaviorally dependent, Group C) and ethanol-naive control rats. All groups were sacrificed 1 month after ethanol withdrawal. The mRNA concentrations of both neuronal glucose transporter 3 and the key glycolytic enzymes phosphofructokinase and pyruvate dehydrogenase were significantly reduced in the hippocampi of the rats behaviorally dependent on ethanol (Group A). No significant changes were seen in any of the remaining brain regions (e.g., cortical areas, limbic forebrain, amygdala, midbrain) in Group A, or in any brain area at all in Groups B and C. The results show that chronic consumption of ethanol in a free-choice situation may impair neuronal glucose uptake and glycolytic flux. This effect is manifested exclusively in the hippocampus and is specifically related to the development of behavioral dependence, since it was not found after forced administration of large amounts of ethanol (Group C).
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PMID:Gene expression of glucose transporters and glycolytic enzymes in the CNS of rats behaviorally dependent on ethanol. 1003 12

The glucose-fatty acid cycle of Randle entails two elements: decreased pyruvate dehydrogenase (PDH) activity, which inhibits glucose oxidation, and inhibition of phosphofructokinase (PFK) by a rise in citrate so that glucose-6-phosphate (G-6-P) levels increase, thereby inhibiting hexokinase activity and hence glucose utilization. Chronic exposure of islets to long-chain fatty acids (FA) is reported to lower PDH activity, but the effect on glucose oxidation and glucose-induced insulin secretion is uncertain. We investigated rat islets that were cultured for 4 days with 0.25 mmol/l oleate/5.5 mmol/l glucose. Glucose oxidation was doubled at 2.8 mmol/l glucose and unchanged at 27.7 mmol/l glucose in the FA-cultured islets despite a 35% decrease in assayed PDH activity. Pyruvate content was increased 60%, which may well compensate for the decreased PDH activity and maintain flux through the citric acid cycle. However, a greater diversion of pyruvate metabolism through the pyruvate-malate shuttle is suggested by unchanged pyruvate carboxylase Vmax and a fourfold higher release of malate from isolated mitochondria. The FA-cultured islets also showed increased basal glucose usage and insulin secretion together with a lowered level of G-6-P and 50% reductions in citrate synthase Vmax and the citrate content. Thus, the effects of chronic FA exposure on islet glucose metabolism differ from the glucose-fatty acid interactions reported in some other tissues.
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PMID:Glucose-fatty acid cycle to inhibit glucose utilization and oxidation is not operative in fatty acid-cultured islets. 1048 Jun 4

Selective breeding is an important tool in behavioral genetics and evolutionary physiology, but it has rarely been applied to the study of exercise physiology. We are using artificial selection for increased wheel-running behavior to study the correlated evolution of locomotor activity and physiological determinants of exercise capacity in house mice. We studied enzyme activities and their response to voluntary wheel running in mixed hindlimb muscles of mice from generation 14, at which time individuals from selected lines ran more than twice as many revolutions per day as those from control (unselected) lines. Beginning at weaning and for 8 wk, we housed mice from each of four replicate selected lines and four replicate control lines with access to wheels that were free to rotate (wheel-access group) or locked (sedentary group). Among sedentary animals, mice from selected lines did not exhibit a general increase in aerobic capacities: no mitochondrial [except pyruvate dehydrogenase (PDH)] or glycolytic enzyme activity was significantly (P < 0.05) higher than in control mice. Sedentary mice from the selected lines exhibited a trend for higher muscle aerobic capacities, as indicated by higher levels of mitochondrial (cytochrome-c oxidase, carnitine palmitoyltransferase, citrate synthase, and PDH) and glycolytic (hexokinase and phosphofructokinase) enzymes, with concomitant lower anaerobic capacities, as indicated by lactate dehydrogenase (especially in male mice). Consistent with previous studies of endurance training in rats via voluntary wheel running or forced treadmill exercise, cytochrome-c oxidase, citrate synthase, and carnitine palmitoyltransferase activity increased in the wheel-access groups for both genders; hexokinase also increased in both genders. Some enzymes showed gender-specific responses: PDH and lactate dehydrogenase increased in wheel-access male but not female mice, and glycogen phosphorylase decreased in female but not in male mice. Two-way analysis of covariance revealed significant interactions between line type and activity group; for several enzymes, activities showed greater changes in mice from selected lines, presumably because such mice ran more revolutions per day and at greater velocities. Thus genetic selection for increased voluntary wheel running did not reduce the capability of muscle aerobic capacity to respond to training.
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PMID:Effects of voluntary activity and genetic selection on muscle metabolic capacities in house mice Mus domesticus. 1100 2

Regulation of carbohydrate and fat utilization by skeletal muscle at rest and during exercise has been the subject of investigation since the early 1960s when Randle et al. proposed the so-called glucose-fatty acid cycle to explain the reciprocal relationship between carbohydrate and fat metabolism. The suggested mechanisms were based on the premise that an increase in fatty acid (FA) availability would result in increased fat metabolism and inhibition of carbohydrate metabolism. Briefly, accumulation of acetyl-CoA would result in inhibition of pyruvate dehydrogenase (PDH), accumulation of citrate would inhibit phosphofructokinase (PFK), and accumulation of glucose-6-phosphate (G6P) would reduce hexokinase (HK) activity. Ultimately, this would inhibit carbohydrate metabolism with increasing availability and oxidation of FA. Although there is some evidence for the existence of the glucose-FA cycle at rest and during low-intensity exercise, it cannot explain substrate use at moderate to high exercise intensities. More recently, evidence has accumulated that increases in glycolytic flux may decrease fat metabolism. Potential sites of regulation are the transport of FA into the sarcoplasma, lipolysis of intramuscular triacylglycerol (IMTG) by hormone-sensitive lipase (HSL), and transport of FA across the mitochondrial membrane. There are several potential regulators of fat oxidation: first, malonyl-CoA concentration, which is formed from acetyl-CoA, catalyzed by the enzyme acetyl-CoA carboxylase (ACC), which in turn will inhibit carnitine palmitoyl transferase I (CPT I). Another possible mechanism is accumulation of acetyl-CoA that will result in acetylation of the carnitine pool, reducing the free carnitine concentration. This could theoretically reduce FA transport into the mitochondria. There is also some recent evidence that CPT I is inhibited by small reductions in pH that might be observed during exercise at high intensities. It is also possible that FA entry into the sarcolemma is regulated by translocation of FAT/CD36 in a similar manner to glucose transport by GLUT-4. Studies suggest that the regulatory mechanisms may be different at rest and during exercise and may change as the exercise intensity increases. Regulation of skeletal muscle fat metabolism is clearly multifactorial, and different mechanisms may dominate in different conditions.
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PMID:Regulation of fat metabolism in skeletal muscle. 1207 50

Activation of either the calcineurin or the extracellular signal-regulated kinase (ERK1/2) pathway increases the percentage of slow fibres in vivo suggesting that both pathways can regulate fibre phenotypes in skeletal muscle. We investigated the effect of calcineurin blockade with cyclosporin A and mitogen-activated protein kinase kinase (MEK1/2) blockade with U0126 upon myosin heavy chain (MHC) isoform mRNA levels and activities of metabolic enzymes after 1 day, 3 days and 7 days of treatment in primary cultures of spontaneously twitching rat skeletal muscle. U0126 treatment significantly decreased MHC Ibeta mRNA levels and significantly increased MHC IIX, MHC IIB, embryonal MHC and perinatal MHC mRNA levels when compared to control. In addition, U0126 treatment significantly increased lactate dehydrogenase, creatine kinase, hexokinase, malate dehydrogenase and beta-hydroxyacyl-CoA dehydrogenase activities above control values while a significant reduction in the percentage of pyruvate dehydrogenase in the active form was also observed. Calcineurin blockade significantly decreased both MHC Ibeta and embryonal mRNA levels below control and significantly increased MHC IIX mRNA levels. Significant increases in the activities of both lactate dehydrogenase and creatine kinase above control values were also seen following cyclosporin A treatment. In conclusion, the results suggest that calcineurin upregulates slow-fibre genes and suppresses fast-fibre genes. Similarly, the ERK1/2 pathway upregulates slow-fibre MHC and suppresses fast-fibre MHC isoforms. However, the effect on enzyme activities is not fibre-type specific. The effect of U0126 on the percentage of pyruvate dehydrogenase in the active form suggests that the ERK1/2 pathway may also be involved in regulation of the phosphorylation state of this enzyme.
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PMID:Blockades of mitogen-activated protein kinase and calcineurin both change fibre-type markers in skeletal muscle culture. 1246 48

After 14 generations of selection for voluntary wheel running, mice from the four replicate selected lines ran, on average, twice as many revolutions per day as those from the four unselected control lines. To examine whether the selected lines followed distinct strategies in the correlated responses of the size and metabolic capacities of the hindlimb muscles, we examined mice from selected lines, housed for 8 wk in cages with access to running wheels that were either free to rotate ("wheel access" group) or locked ("sedentary"). Thirteen of twenty individuals in one selected line (line 6) and two of twenty in another (line 3) showed a marked reduction ( approximately 50%) in total hindlimb muscle mass, consistent with the previously described expression of a small-muscle phenotype. Individuals with these "mini-muscles" were not significantly smaller in total body mass compared with line-mates with normal-sized muscles. Access to free wheels did not affect the relative mass of the mini-muscles, but did result in typical mammalian training effects for mitochondrial enzyme activities. Individuals with mini-muscles showed a higher mass-specific muscle aerobic capacity as revealed by the maximal in vitro rates of citrate synthase and cytochrome c oxidase. Moreover, these mice showed the highest activities of hexokinase and carnitine palmitoyl transferase. Females with mini-muscles showed the highest levels of phosphofructokinase, and males with mini-muscles the highest levels of pyruvate dehydrogenase. As shown by total muscle enzyme contents, the increase in mass-specific aerobic capacity almost completely compensated for the reduction caused by the "loss" of muscle mass. Moreover, the mini-muscle mice exhibited the lowest contents of lactate dehydrogenase and glycogen phosphorylase. Interestingly, metabolic capacities of mini-muscled mice resemble those of muscles after endurance training. Overall, our results demonstrate that during selection for voluntary wheel running, distinct adaptive paths that differentially exploit the genetic variation in morphological and physiological traits have been followed.
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PMID:Artificial selection for high activity favors mighty mini-muscles in house mice. 1252 84

At the onset of exercise, signals from inside and outside the muscle cell increase the availability of carbohydrate (CHO) and fat to provide the fuel required for ATP production. CHO and fat oxidation are the dominant sources of aerobic ATP production and both pathways must be heavily upregulated during exercise to meet the increased energy demand. Within this paradigm, there is room for shifts between the proportion of energy that is provided from CHO and fat. It has long been known that increasing the availability of endogenous or exogenous CHO can increase the oxidation of CHO and decrease the oxidation of fat. The opposite is also true. While descriptive studies documenting these changes are numerous, the mechanisms regulating these shifts in fuel use in the face of constant energy demand have not been thoroughly elucidated. It would be expected, for example, that any fat-induced shift in CHO metabolism would target the enzymes that play key roles in regulating CHO metabolism and oxidation. Inside the muscle these could include glucose uptake (GLUT4) and phosphorylation (hexokinase), glycogenolysis (glycogen phosphorylase), glycolysis (phosphofructokinase) and conversion to acetyl CoA (pyruvate dehydrogenase). The same would be expected for a CHO-induced down regulation of fat metabolism and oxidation and might target transport of long chain fatty acids into the cell (fatty acid translocase CD36), release of fatty acids from intramuscular triacylglycerol (hormone sensitive lipase) and transport into the mitochondria (carnitine palmitoyl transferase complex). This review summarizes the work describing the interaction between CHO and fat metabolism in human skeletal muscle during exercise and presents the theories that may account for CHO/fat interaction during exercise.
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PMID:Regulatory mechanisms in the interaction between carbohydrate and lipid oxidation during exercise. 1286 50

The dauer larva, a non-feeding and developmentally arrested stage of the free-living nematode Caenorhabditis elegans, is morphologically and physiologically specialized for survival and dispersal during adverse growth conditions. The ability of dauer larvae to live several times longer than the continuous developmental life span has been attributed in part to a repressed metabolism. We used serial analysis of gene expression (SAGE) profiles from dauer larvae and mixed growing stages to compare expression patterns for genes with known or predicted roles in glycolysis, gluconeogenesis, glycogen metabolism, the Krebs and glyoxylate cycles, and selected fermentation pathways. Ratios of mixed:dauer transcripts indicated non-dauer enrichment that was consistent with previously determined adult:dauer enzyme activity ratios for hexokinase (glycolysis), phosphoenolpyruvate carboxykinase and fructose 1,6-bisphosphatase (gluconeogenesis), isocitrate dehydrogenase (NADP-dependent), and isocitrate lyase-malate synthase (glyoxylate cycle). Transcripts for the majority of Krebs cycle components were not differentially represented in the two profiles. Transcript abundance for pyruvate kinase, alcohol dehydrogenase, a putative cytosolic fumarate reductase, two pyruvate dehydrogenase components, and a succinyl CoA synthetase alpha subunit implied that anaerobic pathways were upregulated in dauer larvae. Generation of nutritive fermentation byproducts and the moderation of oxidative damage are potential benefits of a hypoxic dauer interior.
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PMID:SAGE surveys C. elegans carbohydrate metabolism: evidence for an anaerobic shift in the long-lived dauer larva. 1287 42


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