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)

1. Time-curves of insulin effects on energy-producing systems in different cellular compartments of rat diaphragm muscle have revealed: (a) a rapid (within minutes) and transient stimulatory effect of insulin on cytoskeletal phosphofructokinase and aldolase and mitochondrial hexokinase. (b) A slower and consistent stimulatory effect on glucose 1,6-bisphosphate level, with concomitant gradual activation of cytosolic phosphofructokinase. Fructose 2,6-bisphosphate levels were not changed by insulin. (c) Lactate concentration correlated with the stimulation of cytoskeletal and cytosolic glycolysis. 2. Calmodulin antagonists, trifluoperazine or CGS 9343B, prevented all these effects of insulin. 3. These results suggest that cytoskeletal glycolysis and mitochondrial oxidation are the source of ATP for the rapid actions of insulin, whereas cytosolic glycolysis is the source of ATP for the slow actions of insulin. Calmodulin is involved in all these effects of insulin.
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PMID:Sequence of insulin effects on cytoskeletal and cytosolic phosphofructokinase, mitochondrial hexokinase, glucose 1,6-bisphosphate and fructose 2,6-bisphosphate levels, and the antagonistic action of calmodulin inhibitors, in diaphragm muscle. 139 93

We show that a rise in cytosolic-free Ca2+ in muscle, induced by Ca(2+)-ionophore A23187 or by the Ca(2+)-mobilizing hormones serotonin, vasopressin, and bradykinin, increases the binding of hexokinase to mitochondria in muscle. This increase could be prevented by treatment with the calmodulin antagonists trifluoperazine or CGS 9343B (a novel, potent, and selective inhibitor of calmodulin activity) which strongly suggests that calmodulin is involved in the Ca(2+)-induced binding of the enzyme to muscle mitochondria.
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PMID:Ca(2+)-ionophore A23187 and the Ca(2+)-mobilizing hormones serotonin, vasopressin, and bradykinin increase mitochondrially bound hexokinase in muscle. 151 75

1. Aluminum is an established neurotoxin. Prolonged exposure to even low levels of aluminum permit its chelation and subsequent transport to brain where it is non-uniformly distributed. 2. Available evidence suggests that (i) aluminum interferes with glucose metabolism by inhibiting hexokinase and glucose-6-phosphate dehydrogenase; (ii) it binds to calmodulin and affects numerous phosphorylation-dephosphorylation reactions; (iii) it binds to transferrin and ferritin, affects the function of these proteins which in turn affect iron metabolism. 3. Thus accumulation of aluminum-induced metabolic errors colocalized in specific areas of the brain may lead to neurological disorders.
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PMID:Neurochemical hypothesis: participation by aluminum in producing critical mass of colocalized errors in brain leads to neurological disease. 167 37

KT5926, (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-14-n-propoxy-2,3 ,9, 10-tetrahydro-8,11-epoxy, 1H,8H, 11H-2,7b,11a-triazadibenzo[a,g]cycloocta[cde] trinden-1-one, was found to be a potent and selective inhibitor of myosin light chain kinase. The compound inhibited both Ca2+/calmodulin-dependent and -independent smooth muscle myosin light chain kinases to a similar extent. The inhibition was not affected by the concentration of calmodulin. Kinetic analyses showed that the mode of inhibition was of the competitive type with respect to ATP (Ki, 18 nM) and of the noncompetitive type with respect to myosin light chain (Ki, 12 nM). These results indicated that KT5926 directly interacted with the enzyme at the catalytic site. KT5926 also inhibited other protein kinases, but with relatively high Ki values; the values for protein kinase C, cAMP-dependent protein kinase, and cGMP-dependent protein kinase were 723, 1200, and 158 nM, respectively. Ca2(+)-ATPase, Na+/K(+)-ATPase, hexokinase, and 5'-nucleotidase were not inhibited by KT5926 at less than 10 microM. The effect of KT5926 on serotonin secretion and protein phosphorylation induced by platelet-activating factor or phorbol ester was examined in rabbit platelets. KT5926 inhibited the phosphorylation of a 20-kDa protein but had no effect on the phosphorylation of a 40-kDa protein, thereby indicating that the compound exerts its selective inhibition of myosin light chain kinase in intact cells. The compound inhibited serotonin secretion induced by platelet-activating factor, but its potency was significantly less than that of K-252a, (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9, 10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b, 11a-triazadibenzo[a,g]cycloocta [cde]trinden-1-one, which inhibited the phosphorylation of both the 20-kDa protein and the 40-kDa protein. Phorbol ester-induced secretion was not suppressed by KT5926. These results provide the evidence that both the 20-kDa protein phosphorylation by myosin light chain kinase and the 40-kDa protein phosphorylation by protein kinase C substantially contribute to the secretion response in platelets.
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PMID:KT5926, a potent and selective inhibitor of myosin light chain kinase. 232 35

1. Thioridazine and trifluoperazine, which have been previously found in this laboratory to be the most effective calmodulin antagonists in treatment of burns, are shown here to be also effective in the treatment of frostbite. 2. Electron microscopic studies have revealed a complete reversal of both the vascular and skin tissue damage induced by frostbite. 3. The reversal of the vascular damage was also demonstrated by the ability of these compounds to abolish the increase in hemoglobin content in the skin. 4. The reversal of the skin tissue damage was also revealed by the ability of these compounds to raise the decreased ATP level and the reduced activities of 6-phosphogluconate dehydrogenase and mitochondrial and soluble hexokinase in skin, induced by frostbite, to normal control levels.
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PMID:Treatment of frostbite with the calmodulin antagonists thioridazine and trifluoperazine. 260 33

To what extent can damage to the central and peripheral nervous systems be ascribed to chronic aluminum (Al) intoxication taken as a chelating agent for phosphorus, to limit hyperphosphatemia in uremic patients? Since Al is normally eliminated by the renal route, its accumulation in uremia has to be ascribed to a reduced or abolished renal clearance of the metal, which results in preferential toxicity for certain tissues, especially nervous tissue, which shows difficulty in eliminating Al, even after intake has been stopped. This review discusses, on the basis of toxicologic, experimental and clinical data, the possible pathogenic steps of Al neurotoxicity in uremia, considering: the damage to axonal transport in which Al intoxication tends to affect the components of the cytoskeleton, the polymerization phase of the alpha and beta tubulin constituents of neurotubules, and the normal translocation of neurofilaments from the perikaryon to more distal positions of the axon; the abnormalities in the brain pool of adrenergic, cholinergic and GABA neurotransmitters; the increase in permeability and changes in perm-selectivity of the blood-brain-barrier, with further loss of neurotransmitters and with acquisition, from the systemic circulation, of neurotransmitter-like substances such as hormones, monoamines and peptides, which may adversely modulate synaptic and membrane functions; the cerebral energy metabolism and particularly the hexokinase reaction, by Al replacement of the Mg-ion in the Mg-ATP complex, so that phosphorylation of glucose to G6P is blocked; the interaction of Al with calmodulin by displacement of the Ca-ion and subsequent formation of a stable Al-calmodulin complex with a cytotoxic effect due to the increase in the intracellular calcium concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The physiopathologic bases of the neurotoxicity of phosphorus chelating agents containing soluble aluminum salts in patients with renal insufficiency]. 266 59

1. Several calmodulin antagonists abolished the decrease in ATP level and in the activities of 6-phosphogluconate dehydrogenase and mitochondrial and soluble hexokinase, induced by burns in the rat skin. 2. These antagonists had also a protective action on the blood capillaries and erythrocyte membrane, as judged by the electron microscopic appearance, as well as the abolishment of hemoglobin increase and burn edema. 3. Of all the compounds investigated here, the most effective were trifluoperazine and thioridazine, which are also known as the more potent calmodulin antagonists. 4. The present experiments suggest that calmodulin antagonists may be effective drugs in treatment of burns, having both therapeutic and prophylactic action.
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PMID:Therapeutic and prophylactic treatment of skin burns with several calmodulin antagonists. 271 15

It is shown in experiments on rats that the early postischemic period after 1- and 1.5-hour ischemia of kidneys is characterized by a decrease in the damage of the glycolytic system site which induces glucose-6-phosphate transformation into lactate and by an increase in the inhibition intensity of the initial hexokinase reaction of glycolysis. In the postischemic period after more prolonged (2-, 3-hour) ischemia the damage of the glycolytic system develops also at the site of glucose-6-phosphate transformation into lactate. Administration either of the nucleotide complex (NAD and AMP) or calmodulin inhibitors (aminazine and zinc sulphate) to rats prior to two-hour occlusion of kidneys vessels promotes a decrease in the inhibition of the glycolytic system activity in the postischemic period. At the same time the separate and combined application of zinc sulphate and triftazin (the most intensive calmodulin inhibitor) is not efficient. The positive effect of NAD, AMP and aminazine on the state of the glycolytic kidney system in the postischemic period correlates with the improvement of the blood microcirculation processes in them.
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PMID:[Glycolysis in the rat kidney shortly after ischemia and administration of calmodulin inhibitors, AMP and NAD]. 379 79

The mechanism of retraction of the longitudinal flagellum of Ceratium tripos was studied by making extracted models of the flagellum. Non-detergent models extracted in low ionic strength medium containing 1 M-glucose, 10 mM-EDTA, and 50 mM-Tris X HCl buffer (pH 8.0), retracted when Ca2+, Mg2+, Ba2+, Sr2+, Mn2+ or Cd2+ was applied locally with a glass capillary. A demembranated model of the flagellum was made with an extraction medium containing 0.8-1.0 M-glucose, 20 mM-Tris-acetate (pH 7.8), 2 mM-EGTA, 5-7 mM-MgSO4, 0.1 M-potassium glutamate and 0.1% Triton X-100. The model required a concentration of Mg2+ of a few mmol/l for successful reactivation of both retraction and undulation, and about 0.1 M-potassium glutamate (or sodium glutamate) for reactivation of undulation. Neither type of motion of the models could be reactivated above 35 degrees C. Ca2+ induced the retraction at pCa 5.5 or less. In addition to Ca2+, Mn2+, Ba2+, Sr2+ and Cd2+ also induced retraction but Mg2+, La3+ or Tb3+ did not. Although ATP was required for undulation, it was not required for retraction. Co-incubation with hexokinase to remove contaminating ATP did not suppress the retraction. The potent ATPase inhibitor, orthovanadate, inhibited undulation at 10 micron but did not inhibit retraction even at 2 mM. SH blockers, N-ethylmaleimide and dithio-bis-nitrobenzoic acid strongly suppressed undulation but had no effect on retraction. Calmodulin inhibitors, trifluoperazine and chlorpromazine, also had no effect on retraction. These data indicate that undulation is generated by a 9 + 2 microtubular axoneme using energy released by hydrolysis of ATP and that retraction can be induced by Ca2+ without a requirement for ATP.
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PMID:Extraction model of the longitudinal flagellum of Ceratium tripos (Dinoflagellida): reactivation of flagellar retraction. 385 92

Mg2+-ATPase activity was identified in the cytosol of human erythrocytes. A partial purification of this activity was achieved by an initial DEAE-Sephadex column chromatography, followed by gel filtration on Sephadex G-100 and then a second DEAE-Sephadex chromatography procedure. The enzyme appeared in the void volume of the Sephadex G-100 column and was retained on an Amicon XM100A ultrafiltration membrane. The molecular weight of the enzyme was estimated to be 113 000 from SD gels. The above purification protocol yielded an enzyme with an optimal pH between 7.6 and 8.2. The enzyme activity increased linearly between 30 and 44 degrees C. It was stable for several months at -20 degrees C. Magnesium was essential for activity, but the rate attainable with Mn2+ was at least as great as that due to Mg2+. No other divalent cation was able to substitute for Mg2+ or Mn2+. Neither low nor high Ca2+ concentrations significantly affected the enzymatic activity. Substrate specificity studies showed that ATP was the preferred substrate followed by CTP (46% of the rate produced by ATP). Hydrolysis of GTP, UTP, ITP and ADP was less than 10% of the rate seen with ATP. No phosphatase, pyrophosphatase, phosphodiesterase, hexokinase, phosphofructokinase or adenylate cyclase activity could be detected in this enzyme preparation. Calmodulin, which stimulates the (Ca2+ + Mg2+)-ATPase of the human erythrocyte membrane, failed to enhance the Mg2+-ATPase activity. Of considerable interest, the activity of this Mg2+-ATPase was enhanced approximately 5-fold by low concentrations of mercuric ion, p-hydroxymercuribenzoate and DTNB, but was much less sensitive to iodoacetamide.
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PMID:Partial purification and characterization of a novel Mg2+-dependent ATPase present in the cytosol from human erythrocytes. 615 Jul 30


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