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)

A series of recent experimental findings are reviewed to indicate that glucokinase does not represent the pancreatic B-cell glucoreceptor. Whether in liver, pancreatic islet or insulin-producing tumoral cell homogenates, glucokinase fails to yield a higher reaction velocity with alpha-than beta-D-glucose. At a high glucose concentration (40 mmol/l), when the phosphorylation of glucose by glucokinase is indeed higher with beta- than alpha-D-glucose, no preference for beta-D-glucose is observed in intact islets, as judged from the utilization of D-[5-3H]glucose, production of lactic acid, oxidation of D-[U-14C]glucose, net uptake of 45Ca or release of insulin. The glucose 6-phosphate content of intact islets is higher in the presence of beta- than alpha-D-glucose. At a low glucose concentration (3.3 mmol/l), when the participation of glucokinase to hexose phosphorylation is minimal, alpha-D-glucose is still better metabolized and stimulates both 45Ca net uptake and insulin release more efficiently than beta-D-glucose, despite the fact that hexokinase yields a higher reaction velocity with beta- than alpha-D-glucose. In intact islets, beta-D-glucose is used preferentially to alpha-D-glucose in the pentose cycle pathway as judged from the oxidation of alpha- or beta-D-[1-14C]glucose relative to that of alpha- or beta-D-[6-14C]glucose. In islets removed from fasted rats, the rate of glycolysis is more severely decreased than expected from the repression of glucokinase. The metabolism of glucose in tumoral insulin-producing cells differs, in several respects, from that in normal pancreatic islets, although the pattern of hexokinase and glucokinase activities is similar in these two types of cells. All these observations point to the participation of regulatory sites distal to glucose phosphorylation in the control of glucose metabolism in islet cells.
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PMID:Glucokinase is not the pancreatic B-cell glucoreceptor. 299 60

Saccharomyces cerevisiae glucokinase (GLK) is the only described hexose-phosphorylating enzyme specific for aldo-hexoses. The gene was cloned by complementation of a triple mutant lacking all hexose-phosphorylating isoenzymes. Restriction sites were confirmed by genomic hybridization and GLK1 was mapped on chromosome III by ROFAGE, a method derived from the orthogonal field alteration gel electrophoresis. The mapping data were in agreement with previous genetic data. The open reading frame was established by two transcription start points in front of the initial ATG codon and by C-terminal beta-galactosidase fusions. The mRNA is 1.75 kb long and codes for 500 amino acid (aa) residues. Diversity of GLK from hexokinases PI and PII is very marked, with only 26 and 28% overall aa homology. A central core of about 350 aa shows 39% homology. No cross-hybridization could be observed by Southern hybridization. However, strong homologies were found over a range of 11 aa between glucokinase, yeast hexokinases (PI, PII) and rat hexokinase with 8 aa in common. These strongly conserved homologies give support to the view that this aa region corresponds to the binding site for glucose. Unlike all other hexose-phosphorylating enzymes, there is no proline residue indicating a conformational turn next to this glucokinase region. This finding may explain the failure of fructose phosphorylation. In both GLK and the hexokinases, a lysine residue is also conserved at aa position 110 which probably corresponds to the ATP-binding site. Additionally, a consensus sequence of 8 aa residues which is common for ATP-binding enzymes is conserved within the C-terminal part of GLK. The codon bias index for GLK1 is 0.25, which is very low compared with other glycolytic enzymes described so far. The gene is moderately expressed and constitutive on different carbon sources investigated. GLK1 null alleles had no detectable effects on sporulation and growth. Hence, a physiological role for GLK, which might explain its preservation, could not be detected under our laboratory test conditions.
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PMID:Structure of yeast glucokinase, a strongly diverged specific aldo-hexose-phosphorylating isoenzyme. 307 53

Four different hexokinase (HK) isoenzymes are distributed in different proportions in human tissues. Fibroblasts contain HK type I as the predominant glucose phosphorylating activity, the same isoenzyme that predominates in red blood cells (RBC). We have established cell lines from two patients homozygous for RBC HK deficiency but carrying different mutations. In one case (HK-Melzo) the residual RBC enzyme shows a marked heat instability but possesses normal kinetic and regulatory properties; in the other (HK-Napoli), the enzyme is characterized by an increased Ki for glucose-1,6-diphosphate. These properties are also retained by the fibroblasts' hexokinase. Glucose utilization by cultured fibroblasts from these patients was markedly reduced in the cell lines where HK deficiency was more pronounced. However, cells with only 30% HK activity retained their full ability to utilize glucose in the hexose monophosphate pathway. This was shown to be true not only under basal conditions but also in the presence of oxidative agents such as methylene blue. Significant reduction of the ATP level was also found in HK-Melzo fibroblasts. Thus, HK deficiency is associated with reduced glucose utilization and normal hexose monophosphate shunt rates. Results previously obtained on RBC support similar conclusions.
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PMID:Glucose metabolism in fibroblasts from patients with erythrocyte hexokinase deficiency. 309 19

Mannose toxicity in honeybees is due to a marked shortage of mannosephosphate isomerase that leads to a large accumulation of mannose-6-P and a marked depletion of ATP. Drosophila melanogaster and Ceratitis capitata are insensitive to mannose and have excess of mannosephosphate isomerase over hexokinase. 2-Deoxyglucose is as toxic as mannose for honeybees and is toxic also for the other insects studied, which supports the conclusion that the mechanism of mannose toxicity involves large accumulation of a hexosephosphate.
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PMID:Mechanism of mannose toxicity. 309 20

Human erythrocytes were loaded with homogeneous hexokinase purified from human placenta (an enzyme species apparently identical to the erythrocyte enzyme), using a procedure of encapsulation based on hypotonic hemolysis, isotonic resealing and reannealing. The hexokinase-overloaded erythrocytes contained 4.77 +/- 0.75 IU of hexokinase activity per ml of packed erythrocytes, a value 15-times higher than that of corresponding unloaded or native red cells. The hexokinase-loaded erythrocytes were found to metabolize twice the amount of glucose consumed by the unloaded cells through a nearly doubled glycolytic activity, while the activity of the hexose monophosphate shunt pathway was unmodified. Estimates of glycolytic intermediates showed increased levels of most metabolites with respect to the unloaded erythrocytes, while the intracellular concentrations of adenine nucleotides and 2,3-bisphosphoglycerate were unaffected by entrapment of hexokinase. The new steady-state condition characterized by improved glycolytic function was demonstrated to be directly related to enhanced levels of hexokinase activity and not to the use of a rejuvenation solution during the procedure of entrapment. These results are consistent with suggestions by several investigators that glucose metabolism in human erythrocytes is regulated by hexokinase, and they open new perspectives for manipulating erythrocytes with the ultimate aim of improving their survival under different storage conditions.
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PMID:Improved metabolic properties of hexokinase-overloaded human erythrocytes. 317 33

A mathematical model is presented which comprises the reactions of glycolysis, the hexose monophosphate shunt (HMS) and the glutathione system in erythrocytes. The model is used to calculate stationary and time-dependent metabolic states of the cell in vitro and in vivo. The model properly accounts for the following metabolic features observed in vitro: (a) stimulation of the oxidative pentose pathway after addition of pyruvate due to a NADP-dependent lactate dehydrogenase as coupling enzyme between glycolysis and the oxidative pentose pathway, (b) relative share of the oxidative pentose pathway in the total consumption of glucose amounting to approximately 10% in the normal case and to approximately 90% under conditions of oxidative stress excreted by methylene blue. From the application of the model to in vivo conditions it is predicted that (c) under normal conditions glycolysis and the HMS are independently regulated by the energetic and oxidative load, respectively, (d) under conditions of enhanced energetic or oxidative load both glycolysis and the HMS are mainly controlled by the hexokinase; in this situation the highest possible values of the energetic and oxidative load which are compatible with cell integrity are strongly coupled and considerably restricted in comparison with the normal case, (e) the stationary states possess bifurcation points at high and low values of the energetic load.
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PMID:Interrelations between glycolysis and the hexose monophosphate shunt in erythrocytes as studied on the basis of a mathematical model. 319 Dec 18

Mannose in animal cells is phosphorylated by hexokinase (HK) and later isomerised by mannose phosphate isomerase (MPI) to fructose-6-P, which is incorporated in the glycolysis pathway. In this paper we report a significant decrease of MPI activity in splenic lymphoid cells from AKR/J old mice with lymphocytic leukaemia in comparison to that found in splenic lymphocytes from AKR/J non-leukaemic young mice and BALB/c young and old control mice. However, HK with mannose as substrate presents a normal activity in AKR/J leukaemic mice. This marked shortage of MPI explains the in vitro mannose toxicity found by us here in splenic lymphoid cells from AKR/J leukaemic mice. MPI activity was also decreased in peripheral blood lymphocytes from 4 out of the 6 patients studied with chronic lymphocytic leukaemia in relation to the activity found in the lymphocytes from healthy donors. The utility of analysing MPI activity in leukaemia patients and the use of mannose as an innocuous chemotherapic supporting agent in patients with decreased MPI activity is proposed.
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PMID:Enzymes of mannose metabolism in murine and human lymphocytic leukaemia. 321 65

Rat lenses treated with greater than 0.06 mM hydrogen peroxide (HP) appeared to sustain epithelial damage, particularly a loss of enzymes including hexokinase, which controls the supply of glucose-6-phosphate. This may account for the lower level of hexose monophosphate shunt activation observed in these lenses. Other alterations include a decrease of lactate production and disturbance to ionic balance. These changes occurred despite HP removal by glutathione reductase/peroxidase system, catalase and other mechanisms. This suggests an inherent weakness for the lens to resist stresses from high levels of HP. Further, competition for NADPH between aldose reductase and glutathione reductase apparently affects the lens's ability to detoxify HP. This implies a role for oxidation in diabetic cataractogenesis.
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PMID:The lens's response to exogenous hydrogen peroxide. 322 97

Glucose 6-phosphate as well as several other hexose mono- and diphosphates were found by kinetic studies to be competitive inhibitors of human hexokinase I (ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1) versus MgATP. Limited proteolysis by trypsin does not destroy the hexokinase activity but produces as well-defined peptide map when the digested enzyme is electrophoresed in the presence of sodium dodecyl sulfate. MgATP at subsaturating concentration protects hexokinase from trypsin digestion, while phosphorylated sugars, Mg2+, glucose and inorganic phosphate have no effect. Addition of glucose 6-phosphate to the MgATP-hexokinase complex at a concentration 100-times higher than its Ki was not able to reverse the MgATP-induced conformation of hexokinase, suggesting that the binding of glucose 6-phosphate and MgATP are not mutually exclusive. Similar evidence was also obtained by studies of the induced modifications of ultraviolet spectra of hexokinase by the binding of MgATP, glucose 6-phosphate and both compounds. Among a library of monoclonal antibodies produced against rat brain hexokinase I and that recognize human placenta hexokinase I, one (4A6) was found to be able to modify the Ki of glucose 6-phosphate (from 25 to 140 microM) for human hexokinase I. The same antibody also weakens the inhibition by all the other hexoses phosphate studied without affecting the apparent Km for MgATP (from 0.6 to 0.75 mM) or for glucose. These data support the view for the binding of glucose 6-phosphate at a regulatory site on the enzyme.
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PMID:The interaction of phosphorylated sugars with human hexokinase I. 325 34

Characterization of glucokinase in pancreatic B-cells from ob/ob mice and from rat liver revealed identical characteristics. A narrow substrate specificity; high Km values for the two substrates, D-glucose and D-mannose, in the range of 10 and 20 mmol/l, respectively; higher Vmax values for D-glucose than for D-mannose; inhibition of glucokinase activities by D-mannoheptulose and by a specific glucokinase antibody. These characteristics distinguish glucokinase in soluble cytoplasmic fractions of pancreatic B-cells and liver from low Km hexokinases. Alloxan is a pancreatic B-cell cytotoxic agent, which has been widely used as a tool for the elucidation of the mechanisms of insulin secretion, because its inhibitory action on insulin secretion has been presumed to be intimately related to the mechanism of glucose-induced insulin secretion. Alloxan inhibited glucokinase but not hexokinase activity in cytoplasmic fractions of pancreatic B-cells and liver. The half maximal inhibitory concentration of alloxan was 5 mumol/l. Glucokinase activity was protected from alloxan toxicity only by D-glucose and D-mannose; the alpha anomer of D-glucose provided significantly greater protection than the beta anomer. The non-metabolizable sugar 3-O-methyl-D-glucose did not provide protection of glucokinase activity against inhibition by alloxan. Thus, inhibition of pancreatic B-cell glucokinase may contribute to the inhibition of glucose-induced insulin secretion by alloxan. These results support the contention that glucokinase regulates the metabolic flux rate through the glycolytic chain in the pancreatic B-cell and thereby generates the signal for glucose-induced insulin secretion.
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PMID:Glucokinase in pancreatic B-cells and its inhibition by alloxan. 329 98


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