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)

It is known that ischemia commonly increases exogenous glucose utilization by accelerating glucose uptake and flux rates through the Embden-Meyerhof pathway. Constitutive enzymes regulate the rate of glycolysis and in turn are regulated by product inhibition and allosteric controls. The purpose of this report was to test whether mRNA abundance for select glycolytic enzymes, and glucose transport proteins, is also modified. Six intact working pig hearts with coronary flow controlled by extracorporeal perfusion were compared at the following conditions: (1) aerobic control perfusion; (2) ischemia affected by a 60% decrease in left anterior descending (LAD) coronary perfusion: (3) ischemia again affected by a 60% decrease in LAD flow followed by a 40-min interval of aerobic reflow; (4) an intermittent ischemia and reflow protocol including four cycles of similar LAD flow reductions (5 min per cycle) interspersed with 15-20 min of aerobic reperfusion; (5) a 4-day model designed to produce myocardial chronic hibernation: and (6) mild ischemia induced by a 40% decrease in LAD flow for 85 min to produce certain adaptations compatible with short-term hibernation. In each heart, mRNA abundance was measured from LAD and circumflex (LCF) perfused myocardium for hexokinase, phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase and the two glucose transporter isomers, GLUT 4 and GLUT 1. mRNA data from LAD myocardium in intervention hearts were normalized to those from LAD tissue in the control heart (LADc) and with LCF values in the same intervention hearts. Signal variance around unity in the LAD tissue, with respect to that of the LCF myocardium, in the control heart compared closely (44 and 41% in two separate runs, respectively). GLUT 1/GLUT 4 ratios in the LAD and LCF beds of this heart also agreed closely. LAD/LADc ratios were increased for hexokinase (1.69), phosphofructokinase (3.69), and glyceraldehyde-3-phosphate dehydrogenase (2.29) in the ischemia heart and for phosphofructokinase (3.90), glyceraldehyde-3-phosphate dehydrogenase (2.20), GLUT 4 (1.55) and GLUT 1 (2.20) in the ischemia/reflow heart. There was no evidence of excess signal in the intermittent ischemia/reflow, chronic hibernation, or mild ischemia hearts. Altered signal from LCF myocardium was also suggested. These data indicate that mRNA abundance for select glycolytic enzymes and transporter proteins is increased in ischemic myocardium with or without reperfusion and offers a possible mechanism for increased protein activity in settings of diminished regional coronary flow.
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PMID:mRNA expression of glycolytic enzymes and glucose transporter proteins in ischemic myocardium with and without reperfusion. 992 82

Glucose uptake is autoregulated in a variety of cell types and it is thought that glucose transport is the major step that is subjected to control by sugar availability. Here, we examined the effect of high glucose concentrations on the rate of glucose uptake by human ECV-304 umbilical vein-derived endothelial cells. A rise in the glucose concentration in the medium led a dose-dependent decrease in the rate of 2-deoxyglucose uptake. The effect of high glucose was independent of protein synthesis and the time-course analysis indicated that it was relatively slow. The effect was not due to inhibition of glucose transport since neither the expression nor the subcellular distribution of the major glucose transporter GLUT1, nor the rate of 3-O-methylglucose uptake was affected. The total in vitro assayed hexokinase activity and the expression of hexokinase-I were similar in cells treated or not with high concentrations of glucose. In contrast, exposure of cells to a high glucose concentration caused a marked decrease in phosphorylated 2-deoxyglucose/free 2-deoxyglucose ratio. This suggests the existence of alterations in the rate of in vivo glucose phosphorylation in response to high glucose. In summary, we conclude that ECV304 human endothelial cells reduce glucose utilization in response to enhanced levels of glucose in the medium by inhibiting the rate of glucose phosphorylation, rather than by blocking glucose transport. This suggests a novel metabolic effect of high glucose on cellular glucose utilization.
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PMID:High glucose concentrations inhibit glucose phosphorylation, but not glucose transport, in human endothelial cells. 1035 4

Chronic exposure (48 h) to glucosamine resulted in a dose-dependent reduction of basal and insulin-stimulated glucose uptake activities in human skeletal muscle cell cultures from nondiabetic and type 2 diabetic subjects. Insulin responsiveness of uptake was also reduced. There was no change in total membrane expression of either GLUT1, GLUT3, or GLUT4 proteins. While glucosamine treatment had no significant effects on hexokinase activity measured in cell extracts, glucose phosphorylation in intact cells was impaired after treatment. Under conditions where glucose transport and phosphorylation were down regulated, the fractional velocity (FV) of glycogen synthase was increased by glucosamine treatment. Neither the total activity nor protein expression of glycogen synthase were influenced by glucosamine treatment. The stimulation of glycogen synthase by glucosamine was not due totally to soluble mediators. Reflective of the effects on transport/phosphorylation, total glycogen content and net glycogen synthesis were reduced after glucosamine treatment. These effects were similar in nondiabetic and type 2 cells. In summary: 1) Chronic treatment with glucosamine reduces glucose transport/phosphorylation and storage into glycogen in skeletal muscle cells in culture and impairs insulin responsiveness as well. 2) Down-regulation of glucose transport/phosphorylation occurs at a posttranslational level of GLUTs. 3) Glycogen synthase activity increases with glucosamine treatment. 4) Nondiabetic and type 2 muscle cells display equal sensitivity and responsiveness to glucosamine. Increased exposure of skeletal muscle to glucosamine, a substrate/precursor of the hexosamine pathway, alters intracellular glucose metabolism at multiple sites and can contribute to insulin resistance in this tissue.
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PMID:Glucosamine regulation of glucose metabolism in cultured human skeletal muscle cells: divergent effects on glucose transport/phosphorylation and glycogen synthase in non-diabetic and type 2 diabetic subjects. 1046 66

Insulin resistance seems to be a metabolic aberration associated with obesity. Impaired insulin action is also central to a cluster of diseases including non-insulin dependent diabetes, hypertension, dyslipidemias and atherosclerosis. Body fat distribution, especially upper body segment obesity is related to insulin-resistance. Glucose uptake is insulin dependent in skeletal muscle and adipose tissue. From a quantitative standpoint, skeletal muscle has the greater impact on whole body glucose economy, therefore the cause of altered insulin sensitivity has been looked for in this tissue. The skeletal muscle is composed of different types of fibers with specific metabolic and circulatory characteristics; type IIB fibers are less insulin-sensitive and their proportion has been related to obesity and insulin resistance. The different factors that may impair insulin action and alter glucose uptake in skeletal muscle are: lower blood flow to muscle, produced by either decreased vasodilation or by increased sympathetic nerve activity; augmented diffusion distance from capillaries to muscle due to a decrease in capillary number or to enlarged muscle cells; decrease of insulin receptors; change in the fatty acid profile of major membrane structural phospholipids; decrease in glucose transporters (GLUT 4) and/or hexokinase; impairment in metabolic routes of glucose in muscle as reduction in glycogen synthase. Also, the high rate of lipolysis present in obesity and in insulin resistance could lead to an impaired glucose oxidation in muscle.
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PMID:[Obesity, insulin resistance and skeletal muscle characteristics]. 1051 36

We analyzed the structural features of insulin-potentiating fragments of human growth hormone by computative simulations. The peptides were designated from the N-terminus sequences of the hormone positions at 1-15 (hGH(1-15); H2N-Phe1-Pro2-Thr3-Ile4-Pro5-Leu6-Ser7-Arg8-L eu9-Phe10-Asp11-Asn12-Ala13-Met14-Leu15 -COOH), 6-13 (hGH(6-13)), 7-13 (hGH(7-13)) and 8-13 (hGH(8-13)), which enhanced insulin-producing hypoglycemia. In these peptide molecules, ionic bonds were predicted to form between 8th-arginyl residue and 11th-aspartic residue, and this intramolecular interaction caused the formation of a macrocyclic structure containing a tetrapeptide Arg8-Leu9-Phe10-Asp11. The peptide positions at 6-10 (hGH(6-10)), 9-13 (hGH(9-13)) and 10-13 (hGH(10-13)) did not lead to a macrocyclic formation in the molecules, and had no effect on the insulin action. Although beta-Ala13hGH(1-15), in which the 13th-alanine was replaced by a beta-alanyl residue, had no effect on insulin-producing hypoglycemia, the macrocyclic region (Arg8-Leu9-Phe10-Asp11) was observed by the computative simulation. An isothermal vibration analysis of both of beta-Ala13hGH(1-15) and hGH(1-15) peptide suggested that beta-Ala13hGH(1-15) is molecule was more flexible than hGH(1-15); C-terminal carboxyl group of Leu15 easily accessed to Arg8 and inhibited the ionic bond formation between Arg8 and Asp11 in beta-Ala13hGH(1-15). The peptide of hGH(8-13) dose-dependently enhanced the insulin-involved fatty acid synthesis in rat white adipocytes, and stabilized the C6-NBD-PC (1-acyl-2-[6-[(7-nitro-2,1,3benzoxadiazol-4-yl)amino]-caproyl]-sn- glycero-3-phosphatidylcholine) model membranes. In contrast, hGH(9-13) had no effect both on the fatty acid synthesis and the membrane stability. In the same culture conditions as the fatty acid synthesis assay, hGH(8-13) had no effect on the transcript levels of glucose transporter isoforms (GLUT 1, 4) and hexokinase isozymes (HK I, II) in rat white adipocytes. Judging from these results we considered that the macrocyclic structure in human growth hormonal peptides is regarded with the modification of insulin action, and hGH(8-13) is an essential sequence for the modification of insulin action. This hGH(8-13) peptide modifies the insulin action via stabilizing the cell membrane, and does not directly act on the insulin-involved glucose metabolism.
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PMID:Analyses of insulin-potentiating fragments of human growth hormone by computative simulation; essential unit for insulin-involved biological responses. 1097 21

Uteroplacental insufficiency causes intrauterine growth retardation (IUGR) and subsequent low birth weight, which predisposes the affected newborn towards adult Syndrome X. Individuals with Syndrome X suffer increased morbidity from adult ischemic heart disease. Myocardial ischemia initiates a defensive increase in cardiac glucose metabolism, and individuals with Syndrome X demonstrate reduced insulin sensitivity and reduced glucose uptake. Glucose transporters GLUT1 and GLUT4 facilitate glucose uptake across cardiac plasma membranes, and hexokinase II (HKII) is the predominant hexokinase isoform in adult cardiac tissue. We therefore hypothesized that GLUT1, GLUT4 and HKII gene expression would be reduced in heart muscle of growth-retarded rats, and that reduced gene expression would result in reduced myocardial glucose uptake. To prove this hypothesis, we measured cardiac GLUT1 and GLUT4 mRNA and protein in control IUGR rat hearts at day 21 and at day 120 of life. HKII mRNA quantification and 2-deoxyglucose-uptake studies were performed in day-120 control and IUGR cardiac muscle. Both GLUT1 and GLUT4 mRNA and protein were significantly reduced at day 21 and at day 120 of life in IUGR hearts. HKII mRNA was also reduced at day 120. Similarly, both basal and insulin-stimulated glucose uptake were significantly reduced in day-120 IUGR cardiac muscle. We conclude that adult rats showing IUGR as a result of uteroplacental insufficiency express significantly less cardiac GLUT1 and GLUT4 mRNA and protein than control animals (which underwent sham operations), and that this decrease in gene expression occurs in parallel with reduced myocardial glucose uptake. We speculate that this reduced GLUT gene expression and glucose uptake contribute towards mortality from ischemic heart disease seen in adults born with IUGR.
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PMID:Myocardial gene expression of glucose transporter 1 and glucose transporter 4 in response to uteroplacental insufficiency in the rat. 1131 53

Transcript levels of hexokinase (HK) isozymes and glucose transporter (GLUT) isoforms in RNA samples of AH130 cells obtained from dish cultures and ascites were evaluated in a quantitative manner. In AH130 cells cultured in dishes, HKI and HKII were expressed at a similar level, but HKIII and HKIV were not. GLUT1 and GLUT3 were also expressed, and messages of these two isoforms represented 27% and 71%, respectively, of the total GLUT messages. A faint signal of GLUT2 was also observed. On the contrary, in cells grown as ascites, the transcript of HKII was dominant, and its level was about 15-fold over that of dish-cultured AH130 cells. Transcript levels of GLUT1 and GLUT3 were 4.5- and 2-fold, respectively, higher than those in dish-cultured cells. Thus, GLUT1 was more susceptible to changes in culture conditions than GLUT3. Based on these results, we concluded that the change in growth conditions caused synchronized changes in the transcript levels of HKII and GLUT1 in AH130 cells. However, such marked changes in the transcript levels of HKII and GLUT1 were not observed when AH130 cells were cultured in dishes under a hypoxic condition, indicating that the observed changes were not solely attributable to the difference in oxygen concentration between the ascites and cell culture conditions. Accordingly, other factors such as growth factors may be responsible for this difference in levels of HKII and GLUT1 between the two growth conditions.
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PMID:Growth condition-dependent synchronized changes in transcript levels of type II hexokinase and type 1 glucose transporter in tumor cells. 1134 71

This study investigates the relationship between FDG uptake as determined by positron emission tomography (PET) imaging and rates of tumor growth, cellular GLUT1 transporter density, and the activities of hexokinase and glucose-6-phosphatase in a solid tumor implant model. Five different human colorectal xenografts of different growth properties were implanted in athymic rats and evaluated by dynamic (18)F-FDG-PET. The phosphorylating and dephosphorylating activities of the key glycolytic enzymes, hexokinase and glucose-6-phosphatase, were measured in these tumor types by spectrophotometric assays and the expression of GLUT1 glucose transporter protein was determined by immunohistochemistry. Correlations among FDG accumulation, hexokinase activity, and tumor doubling time are reported in these colon xenografts. The results indicate that the activity of tumor hexokinase may be a marker of tumor growth rate that can be determined by (18)F-FDG-PET imaging. PET scanning may not only be a useful tool for staging patients for extent of disease, but may provide important prognostic information concerning the proliferative rates of malignancies.
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PMID:Using positron emission tomography with [(18)F]FDG to predict tumor behavior in experimental colorectal cancer. 1149 12

The effect of membrane-acting agents, biscoclaurine alkaloids (cepharanthine, tetrandrine, isotetrandrine), carbobenzoxy-D-Phe-L-Phe-Gly (z-FFG), and tyrphostin AG17, on the insulin-involved fatty acid synthesis by an beta-agonist (e.g., isoproterenol) in adipocytes was examined. The alkaloids dose-dependently enhanced the insulin-involved fatty acid synthesis in rat white adipocytes, stabilized the C(6)-NBD-PC (1-acyl-2-[6-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-caproyl]-sn-glycero-3-phosphatidylcholine) model membrane, and suppressed the phospholipase A(2)-induced phospholipid degradation. In contrast, z-FFG had no effect on the fatty acid synthesis or the membrane stability. Tyrphostin AG17 suppressed insulin action, but promoted the model membrane stabilization. In the same culture conditions as for the fatty acid synthesis assay, cepharanthine, z-FFG and tyrphostin AG17 had no effect on the transcript levels of glucose transporter isoforms (GLUT 1, 4) and hexokinase isozymes (HK I, II) in rat white adipocytes. Thus, these membrane-acting agents modify the insulin action via a change in the cell membrane condition, and do not directly act on the insulin-involved glucose metabolism. Then we analyzed the structural conformation of these membrane-acting agents by computational simulations. The alkaloids had an elliptic macrocyclic structure, and the order of ellipticity (cepharanthine>tetrandrine>isotetrandrine) agreed with that of the modifying ability for insulin action. The distribution of electrostatic potential fields of these alkaloids was essentially equal by turn in surrounding with the dipole moments. Both in z-FFG and tyrphostin AG17, the distribution pattern of electrostatic potential fields was different from that of the alkaloids. Judging from these results, we concluded that the electrostatic potential field is a good index of the modification of insulin action, and the elliptic structure in these alkaloids is regarded with the modification of insulin action.
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PMID:Modification of cell response to insulin by membrane-acting agents in rat white adipocytes: analysis of structural features by computational simulation. 1159 85

Fluorine-18 fluoro-2-deoxyglucose ((18)FDG) and carbon-14 2-deoxyglucose ((14)C-2-DG) are both widely used tracers of myocardial glucose uptake and phosphorylation. We have recently shown, using positron emission tomography (PET) and nuclear magnetic resonance, that ischaemia-reperfusion (I-R) causes differential changes in their uptake. We describe here the novel application of an autoradiographic technique allowing the investigation of this phenomenon at high resolution, using tracer concentrations of both analogues in the dual-perfused isolated rat heart. We also investigate the importance of glucose transporter (GLUT 1 and GLUT 4) distribution in governing the observed phosphorylated analogue accumulation. Hearts ( n=5) were perfused with Krebs buffer for 40 min, made regionally zero-flow ischaemic for 40 min and reperfused for 60 min with Krebs containing tracer (18)FDG (200 MBq) and tracer (14)C-2-DG (0.37 MBq). Hearts were then frozen and five sections (10 micro m) were cut per heart, fixed and exposed on phosphor storage plates for 18 h (for (18)FDG) and then for a further 9 days (for (14)C-2-DG). Quantitative digital images of tracer accumulation were obtained using a phosphor plate reader. The protocol was repeated in a second group of hearts and GLUT 1 and GLUT 4 distribution analysed. Post-ischaemic accumulation of (18)FDG-6-P was inhibited by 38.2%+/-1.7% and (14)C-DG-6-P by 19.0%+/-2.2%, compared with control ( P<0.05). After placing seven "lines of interrogation" across each heart section and analysing the phosphorylated tracer accumulation along them, a transmural gradient of both tracers was observed; this was highest at the endocardium and lowest at the epicardium. GLUT 4 translocated to the sarcolemma in the ischaemic/reperfused region (from 24%+/-3% to 59%+/-5%), while there was no cellular redistribution of GLUT 1. We conclude that since decreased phosphorylated tracer accumulation occurs after ischaemia-reperfusion, despite greater externalisation of GLUT 4, hexokinase or the affinities of the GLUT transporters are changed under these conditions.
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PMID:Dissociation of glucose tracer uptake and glucose transporter distribution in the regionally ischaemic isolated rat heart: application of a new autoradiographic technique. 1227 16


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