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 compared the metabolism of [1-13C]glucose by wild type cells of Neurospora crassa at normal growth temperature and at heat shock temperatures, using nuclear magnetic resonance analysis of cell extracts. High temperature led to increased incorporation of 13C into trehalose, relative to all other metabolites, and there was undetectable synthesis of glycerol, which was a prominent metabolite of glucose at normal temperature (30 degrees C). Heat shock strongly reduced formation of tricarboxylic acid cycle intermediates, approximately 10-fold, and mannitol synthesis was severely depressed at 46 degrees C, but only moderately reduced at 45 degrees C. A mutant strain of N. crassa that lacks the small alpha-crystallin-related heat shock protein, Hsp30, shows poor survival during heat shock on a nutrient medium with restricted glucose. An analysis of glucose metabolism of this strain showed that, unlike the wild type strain, Hsp30-deficient cells may accumulate unphosphorylated glucose at high temperature. This suggestion that glucose-phosphorylating hexokinase activity might be depressed in mutant cells led us to compare hexokinase activity in the two strains at high temperature. Hexokinase was reduced more than 35% in the mutant cell extracts, relative to wild type extracts. alpha-Crystallin and an Hsp30-enriched preparation protected purified hexokinase from thermal inactivation in vitro, supporting the proposal that Hsp30 may directly stabilize hexokinase in vivo during heat shock.
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PMID:Glucose metabolism in Neurospora is altered by heat shock and by disruption of HSP30. 1007 52

The adipocyte-derived hormone leptin has been reported to inhibit, have no effect, or potentiate insulin secretion in-vitro; these effects mainly depend on the species considered, the concentrations used, and the length of exposure. We investigated the direct effects of recombinant human leptin (HL) on human pancreatic beta cell function by studying insulin secretion (IS), hexokinase and glucokinase activity and Km, and potassium channel permeability in purified human islets (HI). In acute experiments, no effect of 1, 5, 20, or 50 ng/ml HL on glucose or arginine stimulated insulin release was found, whereas 500 ng/ml HL caused a significant decrease of glucose induced IS. After 24h pre-culture with either 20 or 500 ng/ml HL, a significant reduction of glucose (but not arginine) stimulated IS was observed. Exposure to leptin caused a significant increase of potassium channel permeability, whereas hexokinase and glucokinase activity and Km remained unchanged. These results suggest that physiological human leptin concentration is able to importantly affect glucose (but not arginine) stimulated insulin release from human islets only after prolonged exposure. This effect is probably mediated by changes of potassium channel permeability, and is not accompanied by modifications of glucose phosphorylating enzymes properties.
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PMID:Effects of acute or prolonged exposure to human leptin on isolated human islet function. 1008 Sep 51

Truffles are ectomycorrhizal fungi which have a great dependence on carbohydrates supplied by their host plants. The catabolism of hexoses in the mycobiont is important for the production of energy, and the first enzyme in the hexose assimilation pathways is hexokinase. This study reports differences in the expression of this enzyme during the growth of Tuber borchii Vittad. mycelium (strain ATCC 96540). Three hexokinase activities (HKM1, HKM2 and HKM3) were isolated by anion-exchange chromatography and partially purified. HKM1 and HKM2 were present in the linear phase at 15-50 days of growth. Two remarkable differences were found in the sugar-phosphorylating activity and stability of HKM1 and HKM2. HKM2 did not phosphorylate the fructose and it was present in the chromatographic profile only when substrates such as glucose, glucosamine or mannose were added to the extraction buffer. On the contrary, HKM1 utilized also fructose and was detected under all the experimental conditions used. HKM3 was the only molecular form observed after 70 days, when the fungus growth had reached a plateau. To our knowledge these results represent the first evidence for the presence in T. borchii mycelium of three distinct enzymatic forms of hexokinase which are differently expressed during growth of the fungus.
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PMID:Three different forms of hexokinase are identified during Tuber borchii mycelium growth. 1039 Nov 26

Entamoeba histolytica is responsible for amoebic colitis and liver abscess in humans. Entamoeba dispar is a closely related, morphologically indistinguishable nonpathogenic species. The hexokinase (ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1) isoenzyme patterns distinguish the pathogenic and nonpathogenic species. Both species possess two hexokinases with very similar molecular mass and different isoelectric points. In order to understand the role of the two different isoenzymes from E. histolytica, we purified the recombinant hexokinases HXK1 and HXK2 and examined substrate spectrum and kinetic properties. The two enzymes displayed similar temperature and pH optima, they were inhibited strongly by AMP and ADP, not by glucose 6-phosphate. Both enzymes phosphorylated glucose well and were unable to phosphorylate fructose or galactose. We also detected significant differences. HXK1 was more sensitive to inhibition by AMP and ADP. Mannose was phosphorylated well by HXK1, but at a much lower rate by HXK2. We attempted to expand the substrate spectrum of E. histolytica HXK1 by modifying its active site to become similar to the active site of the fructose phosphorylating yeast hexokinase PII. None of the nine mutants gained any fructokinase activity, but all of them retained at least some glucokinase and mannokinase activity. Mannokinase activity was decreased drastically by two single amino acid exchanges, both of which contributed significantly to this effect. The data indicate that a complex interaction of a number of amino acid residues is necessary for the ability to phosphorylate a given hexose.
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PMID:Differences in substrate specificity and kinetic properties of the recombinant hexokinases HXK1 and HXK2 from Entamoeba histolytica. 1061

The low-affinity glucose phosphorylating enzyme glucokinase has the function of a physiological glucose sensor in pancreatic beta cells and in liver. In contrast to the high-affinity hexokinase types I-III glucokinase shows extraordinary sensitivity toward SH group oxidizing compounds. To characterize the function of sulfhydryl groups cysteine residues in the vicinity of the sugar binding site (Cys 213, Cys 220, Cys 230, Cys 233, and Cys 252) as well as cysteine residues a distance from the active site (Cys 364, Cys 371, and Cys 382), they were replaced in human beta cell glucokinase by serine through site-directed mutagenesis. Controlled proteolysis of wild-type glucokinase by proteinase K revealed that the SH group oxidizing agent alloxan can induce the formation of multiple intramolecular disulfide bridges corresponding to a double-band pattern of glucokinase protein in nonreducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The formation of intramolecular disulfide bridges altered the mobility of the protein. None of the cysteine mutations could prevent the formation of the 49-kDa glucokinase conformation after alloxan treatment. The cysteine mutants Cys 233, Cys 252, and Cys 382 showed nearly complete loss of catalytic activity, whereas the V(max) values of the Cys 213, Cys 220, Cys 364, and Cys 371 mutants were decreased by 30-60%. Only the Cys 230 mutant showed kinetic characteristics comparable to those of wild-type glucokinase. The sensitivity of the Cys 213, Cys 230, Cys 364, and Cys 371 mutants toward alloxan-induced inhibition of enzyme activity was up to 10-fold lower compared with wild-type glucokinase. d-Glucose and dithiotreitol provided protection against alloxan-induced inhibition of wild-type glucokinase and all catalytically active cysteine mutants. Conclusively our data demonstrate the functional significance of the cysteine residues of beta cell glucokinase for both structural instability of the enzyme and catalytic function. Knowledge of sensitive cysteine targets may help to develop strategies that improve glucokinase enzyme function under conditions of oxidative stress.
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PMID:Importance of cysteine residues for the stability and catalytic activity of human pancreatic beta cell glucokinase. 1070 Mar 81

We have established two sublines derived from the insulin-secreting mouse pancreatic beta-cell line MIN6, designated m9 and m14. m9 Cells exhibit glucose-induced insulin secretion in a concentration-dependent manner, whereas m14 cells respond poorly to glucose. In m14 cells, glucose consumption and lactate production are enhanced, and ATP production is largely through nonoxidative pathways. Moreover, lactate dehydrogenase activity is increased, and hexokinase replaces glucokinase as a glucose-phosphorylating enzyme. The ATP-sensitive K(+) channel activity and voltage-dependent calcium channel activity in m14 cells are reduced, and the resting membrane potential is significantly higher than in m9 cells. Thus, in contrast to m9, a model for beta-cells with normal insulin response, m14 is a model for beta-cells with impaired glucose-induced insulin secretion. By mRNA differential display of these sublines, we found 10 genes to be expressed at markedly different levels. These newly established MIN6 cell sublines should be useful tools in the analysis of the genetic and molecular basis of impaired glucose-induced insulin secretion.
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PMID:Insulin secretion and differential gene expression in glucose-responsive and -unresponsive MIN6 sublines. 1100 58

The extracellular proteases of Aspergillus nidulans are produced in response to limitation of carbon, nitrogen, or sulfur, even in the absence of exogenous protein. Mutations in the A. nidulans xprF and xprG genes have been shown to result in elevated levels of extracellular protease in response to carbon limitation. The xprF gene was isolated and sequence analysis indicates that it encodes a 615-amino-acid protein, which represents a new type of fungal hexokinase or hexokinase-like protein. In addition to their catalytic role, hexokinases are thought to be involved in triggering carbon catabolite repression. Sequence analysis of the xprF1 and xprF2 alleles showed that both alleles contain nonsense mutations. No loss of glucose or fructose phosphorylating activity was detected in xprF1 or xprF2 mutants. There are two possible explanations for this observation: (1) the xprF gene may encode a minor hexokinase or (2) the xprF gene may encode a protein with no hexose phosphorylating activity. Genetic evidence suggests that the xprF and xprG genes are involved in the same regulatory pathway. Support for this hypothesis was provided by the identification of a new class of xprG(-) mutation that suppresses the xprF1 mutation and results in a protease-deficient phenotype.
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PMID:The Aspergillus nidulans xprF gene encodes a hexokinase-like protein involved in the regulation of extracellular proteases. 1110 57

POP2 protein of Saccharomyces cerevisiae is a component of a protein complex that regulates the transcription of many genes. We found that the 97th threonine residue (Thr 97) of Pop2p was phosphorylated upon glucose limitation. The Thr 97 phosphorylation occurred within 2 min after removing glucose and was reversed within 1 min after the readdition of glucose. The effects of hexokinase mutations and glucose analogs indicate that this phosphorylation is dependent on glucose phosphorylating activity. We purified a protein kinase that phosphorylates a peptide containing Thr 97 of Pop2p and identified it as Yak1p, a DYRK family kinase. Phosphorylation of Pop2p was barely detectable in a yak1Delta strain. We found that Yak1p interacted with Bmh1p and Bmh2p only in the presence of glucose. A GFP-Yak1p fusion protein shuttled rapidly between the nucleus and the cytoplasm in response to glucose. A strain with alanine substituted for Thr 97 in Pop2p showed overgrowth in the postdiauxic transition and failed to stop the cell cycle at G(1) phase in response to glucose deprivation. Thus, Yak1p and Pop2p are part of a novel glucose-sensing system in yeast that is involved in growth control in response to glucose availability.
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PMID:Yak1p, a DYRK family kinase, translocates to the nucleus and phosphorylates yeast Pop2p in response to a glucose signal. 1135 66

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

Two glucose-phosphorylating enzymes, a hexokinase phosphorylating both glucose and fructose, and a glucose-specific glucokinase were electrophoretically separated in the methylotrophic yeast Hansenula polymorpha. Hexokinase-negative, glucokinase-negative and double kinase-negative mutants were isolated in H. polymorpha by using mutagenesis, selection and genetic crosses. Regulation of synthesis of the sugar-repressed alcohol oxidase, catalase and maltase was studied in different hexose kinase mutants. In the wild type and in mutants possessing either hexokinase or glucokinase, glucose repressed the synthesis of maltase, alcohol oxidase and catalase. Glucose repression of alcohol oxidase and catalase was abolished in mutants lacking both glucose-phosphorylating enzymes (i.e. in double kinase-negative mutants). Thus, glucose repression in H. polymorpha cells requires a glucose-phosphorylating enzyme, either hexokinase or glucokinase. The presence of fructose-phosphorylating hexokinase in the cell was specifically needed for fructose repression of alcohol oxidase, catalase and maltase. Hence, glucose or fructose has to be phosphorylated in order to cause repression of the synthesis of these enzymes in H. polymorpha suggesting that sugar repression in this yeast therefore relies on the catalytic activity of hexose kinases.
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PMID:Sugar repression in the methylotrophic yeast Hansenula polymorpha studied by using hexokinase-negative, glucokinase-negative and double kinase-negative mutants. 1150 18


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