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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gamma-aminobutyric acid transporter of rat brain synaptic vesicles was reconstituted in proteoliposomes, and its activity was studied in response to artificially created membrane potentials or proton gradients. Changes of the membrane potential were monitored using the dyes oxonol VI and 3,3'-diisopropylthiodicarbocyanine iodide, and changes of the H+ gradient were followed using acridine orange. An inside positive membrane potential was generated by the creation of an inwardly directed K+ gradient and the subsequent addition of valinomycin. Under these conditions, valinomycin evoked uptake of [3H]GABA which was saturable. Similarly, [3H]glutamate uptake was stimulated by valinomycin, indicating that both transporters can be driven by the membrane potential. Proton gradients were generated by the incubation of K(+)-loaded proteoliposomes in a buffer free of K+ or Na+ ions and the subsequent addition of nigericin. Proton gradients were also generated via the endogenous H+ ATPase by incubation of K(+)-loaded proteoliposomes in equimolar K+ buffer in the presence of valinomycin. These proton gradients evoked nonspecific, nonsaturable uptake of GABA and beta-alanine but not of glycine in proteoliposomes as well as protein-free liposomes. Therefore, transporter activity was monitored using glycine as an alternative substrate. Proton gradients generated by both methods elicited saturable glycine uptake in proteoliposomes. Together, our data confirm that the vesicular GABA transporter can be energized by both the membrane potential and the pH gradient and show that transport can be achieved by artificial gradients independently of the endogenous proton ATPase.
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PMID:Functional reconstitution of the gamma-aminobutyric acid transporter from synaptic vesicles using artificial ion gradients. 168 90

Interactions with the hepatic cytochrome P-450 microsomal enzyme system, as evidenced by statistically significant changes in pharmacokinetic parameters, have been described with some H2-receptor antagonists. Omeprazole is the first of a new class of antisecretory agents inhibiting gastric secretion by blocking hydrogen potassium ATPase. Omeprazole contains a benzimidazole moiety and thus has the potential to interact with the cytochrome P-450 enzyme group. In vitro, in vivo and human clinical studies have assessed whether such an interaction occurs, and the potential clinical consequences, in patients receiving omeprazole therapy. In vitro studies have demonstrated that omeprazole influences O-deethylation and N-demethylation in liver microsomes and the clearance and elimination half-life of antipyrine in isolated perfused liver preparations. Overall, the studies reviewed suggest that omeprazole has a differential affinity toward specific cytochrome P-450 isozymes. In vivo animal studies have demonstrated that omeprazole prolongs pentobarbital sleep times and half-life and decreases [14C]-aminopyrine elimination. Human clinical studies have not demonstrated the "all or none" effect of omeprazole on cytochrome P-450-mediated drug interactions, as is seen with cimetidine. These studies confirm in vitro findings that omeprazole is a differential inhibitor of drug metabolism: interactions have been demonstrated with the model drugs aminopyrine and antipyrine, and the therapeutic drugs diazepam, phenytoin, and warfarin but not with theophylline or propranolol. Although caution should be exercised when initiating omeprazole therapy in patients taking concomitant diazepam, warfarin, and phenytoin, clinically significant drug interactions appear unlikely.
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PMID:Clinical implications of drug interactions with the cytochrome P-450 enzyme system associated with omeprazole. 174 33

Intrinsic factor is produced by the gastric parietal cell. Its secretion is stimulated via all pathways known to stimulate gastric acid secretion: histamine, gastrin, and acetylcholine. There is, however, a different mode of secretion for both substances: atropine, vagotomy, and H2 receptor antagonists inhibit both intrinsic factor and acid secretion, but secretin and the hydrogen-potassium ATPase antagonist omeprazole have no effect on intrinsic factor while substantially reducing acid secretion. Cobalamin in food is bound to animal protein. Cobalamin deficiency due to inadequate dietary intake is rarely seen in extreme vegetarians (vegans). In the stomach cobalamin is liberated from its protein binding by peptic digestion and bound to R-proteins. Hypochlorhydria or achlorhydria, whether medically induced or not, may impair cobalamin uptake. The cobalamin-R-protein complex is split by pancreatic enzymes in the duodenum, where cobalamin is bound to intrinsic factor. Pancreatic insufficiency may lead to cobalamin deficiency. Lack of intrinsic factor is the commonest cause of cobalamin deficiency; very rarely, aberrant forms of intrinsic factor are produced, but the clinical syndrome is similar. Gram-negative anaerobe bacteria bind the cobalamin-intrinsic factor complex, and bacterial overgrowth of the small intestine diminishes cobalamin resorption. Parasitic infections with fish tape-worm and Giardia lamblia are also associated with cobalamin malabsorption. The cobalamin-intrinsic factor complex binds to the ileal receptors in the terminal ileum. Cobalamin absorption may be impaired after resection or by diseases affecting more than 50 cm of the terminal ileum, such as Crohn's disease, coeliac disease, tuberculosis, lymphoma or radiation. There is clearly a wide diversity in the aetiology of cobalamin deficiency, which requires a versatile diagnostic approach.
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PMID:Intrinsic factor secretion and cobalamin absorption. Physiology and pathophysiology in the gastrointestinal tract. 177 33

Vacuolar proton pumps acidify several intracellular membrane compartments in the endocytic pathway. We have examined the distribution of the vacuolar H+ ATPase in LLC-PK1 cells and the structure of the biosynthetically labeled enzyme in membrane fractions enriched for endosomes or lysosomes. LLC-PK1 cells were allowed to internalize cytochrome c-coated colloidal gold as a marker for endocytic compartments. Proton pumps were identified in these cells by staining the cells with a monoclonal antibody against the vacuolar pump detected with either immunogold or immunoperoxidase techniques. H+ ATPase labeling was seen on structures resembling endosomes and lysosomes, but not on Golgi or plasma membrane. To examine the structure of the H+ ATPase in these compartments, we labeled LLC-PK1 cells for 24 h with [35S]methionine and used a Percoll gradient to obtain fractions enriched for endosomes or lysosomes. H+ ATPase immunoprecipitated from both fractions with monoclonal anti-H+ ATPase antibodies had labeled polypeptides of 70, 56, and 31 kDa. On two-dimensional gels, a comparison of the H+ ATPase from the endosomal and lysosomal fractions revealed that the 70-, 56-, and 31-kDa subunits were similar in both fractions. The results show that the vacuolar H+ ATPase in these cells is distributed primarily in endosomes and lysosomes and that the structure of the enzyme is similar in both compartments.
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PMID:Distribution and structure of the vacuolar H+ ATPase in endosomes and lysosomes from LLC-PK1 cells. 182 36

Secretory vesicles that accumulate in the temperature-sensitive sec6-4 strain of yeast have been shown to contain a vanadate-sensitive ATPase, presumably en route to the plasma membrane (Walworth, N. C., and Novick, P. J. (1987) J. Cell Biol. 105, 163-174). We have now established this enzyme to be a fully functional form of the PMA1 [H+]ATPase, identical in its catalytic properties to that found in the plasma membrane. In addition, the secretory vesicles are sealed tightly enough to permit the measurement of ATP-dependent proton pumping with fluorescent probes. We have gone on to exploit the vesicles as an expression system for site-directed mutants of the ATPase. For this purpose, a sec6-4 strain has been constructed in which the chromosomal PMA1 gene is under control of the GAL1 promoter; the mutant pma1 allele to be studied is introduced on a centromeric plasmid under the control of a novel heat shock promoter. In galactose medium at 23 degrees C, the wild-type ATPase is produced and supports normal vegetative growth. When the cells are switched to glucose medium at 37 degrees C, however, the wild-type gene turns off, the mutant gene turns on, and secretory vesicles accumulate. The vesicles contain a substantial amount of newly synthesized, plasmid-encoded ATPase (5-10% of total vesicle protein), but only traces of residual wild-type PMA1 ATPase and no detectable mitochondrial ATPase, vacuolar ATPase, or acid or alkaline phosphatase. To test the expression strategy, we have made use of pma1-105 (Ser368----Phe), a vanadate-resistant mutant previously characterized by standard methods (Perlin, D. S., Harris, S. L., Seto-Young, D., and Haber, J. E. (1989) J. Biol. Chem. 264, 21857-21864). In secretory vesicles, as expected, the plasmid-borne pma1-105 allele gives rise to a mutant enzyme with a reduced rate of ATP hydrolysis and a 100-fold increase in Ki for vanadate. Proton pumping is similarly resistant to vanadate. Thus, the vesicles appear well suited for the production and characterization of mutant forms of the PMA1 [H+]ATPase. They should also aid the study of other yeast membrane proteins that are essential for growth as well as heterologous proteins whose appearance in the plasma membrane may be toxic to the cell.
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PMID:Expression of the yeast plasma membrane [H+]ATPase in secretory vesicles. A new strategy for directed mutagenesis. 182 8

Renal hydrogen ion excretion increases with chronic acid loads and decreases with alkali loads. We examined the mechanism of adaptation by analyzing vacuolar proton-translocating adenosine triphosphatase (H+ ATPase) 31-kD subunit protein and mRNA levels, and immunocytochemical distribution in kidneys from rats subjected to acid or alkali loads for 1, 3, 5, 7, and 14 d. Acid- and alkali-loaded rats exhibited adaptive responses in acid excretion, but showed no significant changes in H+ ATPase protein or mRNA levels in either cortex or medulla. In contrast, there were profound adaptive changes in the immunocytochemical distribution of H+ ATPase in collecting duct intercalated cells. In the medulla, H+ ATPase staining in acid-loaded rats shifted from cytoplasmic vesicles to plasma membrane, whereas in alkali-loaded rats, cytoplasmic vesicle staining was enhanced, and staining of plasma membrane disappeared. In the cortical collecting tubule, acid loading increased the number of intercalated cells showing enhanced apical H+ ATPase staining and decreased the number of cells with basolateral or poorly polarized apical staining. The results indicate that both medulla and cortex participate in the adaptive response to acid and alkali loading by changing the steady-state distribution of H+ ATPase, employing mechanisms that do not necessitate postulating interconversion of intercalated cells with opposing polarities.
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PMID:Expression and distribution of renal vacuolar proton-translocating adenosine triphosphatase in response to chronic acid and alkali loads in the rat. 182 94

The inhibitory effects of sulfhydryl reagents on Ca-ATPase activity in the rabbit lens epithelium were assessed. Test compounds used in this study were selected on their ability to cause a calcium increase in cultured lenses. Under conditions in which lenses were cultured in the presence of the test compound, epithelial Ca-ATPase was inhibited markedly by diamide, t-BHP, IAA and slightly by selenite. The findings demonstrated that hydrogen peroxide caused little inhibition of Ca-ATPase in the lens epithelium, both when the intact lens was cultured in the presence of the oxidant or when the epithelial homogenate contained peroxide during the assay of enzyme activity. The study suggests that if a thiol-modifying compound can reach Ca-ATPase or its critical SH groups, inhibition is likely.
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PMID:Effect of thiol reagents on Ca-ATPase in rabbit lens epithelium. 182 95

Effects of reactive oxygen intermediates generated by hypoxanthine plus xanthine oxidase on the Ca(2+)-adenosinetriphosphatase (ATPase) of sarcoplasmic reticulum from bovine aortic smooth muscle were studied. Exogenous hypoxanthine (0.1-100 microM) plus xanthine oxidase (10 mU/ml) produced an hypoxanthine concentration-dependent inhibition of the Ca(2+)-ATPase. The inhibition could be completely blocked by superoxide dismutase (100 U/ml) but not by either mannitol (20 mM) or deferoxamine (100 microM). Direct addition of hydrogen peroxide in the micromolar range did not cause significant inhibition. These results suggest that superoxide is the primary damaging species. Cysteine blocked this inhibition, suggesting possible involvement of sulfhydryl groups in the inhibition mechanism. Additionally, 1.16 +/- 0.17 mU/g wet wt of xanthine oxidase activity was detected in the postnuclear supernatant of bovine aortic smooth muscle, suggesting the existence of a possible intracellular source of superoxide. This value was calculated to be approximately 5 mU/ml by using a usual value of vascular smooth muscle cellular volume. Thus the level of endogenous xanthine oxidase in vascular smooth muscle is comparable with the level of exogenous xanthine oxidase used in the present study. These findings suggest a potential role of xanthine oxidase-generated superoxide in oxidative damage to vascular smooth muscle during a number of pathophysiological conditions.
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PMID:Inhibition of Ca(2+)-ATPase of vascular smooth muscle sarcoplasmic reticulum by reactive oxygen intermediates. 183 1

Addition of hydrogen peroxide (greater than 10 mM) to aerated derepressed cells of S. cerevisiae in the absence of substrate caused a boost of endogenous respiration and both intra- and extracellular acidification, without any significant change in cellular ATP level. Furthermore, a hyperpolarization of the plasma membrane was indicated by an enhanced accumulation of tetraphenylphosphonium in the cells. The extracellular pH attained was as low as 3.5. The acidification could be suspended by the H(+)-ATPase inhibitors diethylstilbestrol and dicyclohexylcarbodiimide and was, in general, associated with an opposite flux of K+. K+ also stimulated the H(+)-ATPase activity in the purified plasma membrane fraction. These results are consistent with the plasma membrane H(+)-ATPase being involved in the H+ extrusion induced by H2O2 in the absence of substrate. Extended exposure of cells to H2O2 led eventually to an arrest of both respiration and ion fluxes that could be again lifted by depolarizing the plasma membrane. Along with differences in the cellular NADH/NAD+ ratio and in the participation of organic acids, this makes the H2O2-induced acidification distinct from that induced by glucose.
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PMID:Activation of the plasma membrane H(+)-ATPase of Saccharomyces cerevisiae by addition of hydrogen peroxide. 183 83

Unilateral ureteral obstruction for 24 h produces an acidification defect in the rat kidney that closely resembles the human disorder. We examined the role of renal vacuolar H(+)-ATPase distribution and content in the generation of the postobstructive abnormality in distal hydrogen ion secretion. Rats were subjected to unilateral ureteral obstruction for 24 h, and the obstructed and contralateral kidneys were removed at 3 h, 5 days, and 10 days after release of the obstruction. The postobstructed and contralateral kidneys and kidneys from sham-operated rats were analyzed for intercalated cell number and subtype and for the cellular distribution of ATPase staining by means of a monoclonal antibody specific for the 31-kDa subunit of the vacuolar H(+)-ATPase. No change in the number or distribution of subtypes was detected in the cortex nor in the outer or inner stripe of the outer medulla. Immunoreactive H(+)-ATPase increased in both the cortex and medulla at 3 h after obstruction, and thereafter it declined to control values. The major morphological changes in H(+)-ATPase staining detected were an alteration in the intracellular distribution of the enzyme, which we refer to as discontinuity of (or "gaps" in) apical staining, and a decrease in the percent of intercalated cells showing a rim (or plasma membrane) staining pattern in the inner medulla. The changes observed may be a morphological representation of the physiological abnormalities underlying the postobstructive acidification defect.
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PMID:Cellular distribution of H(+)-ATPase following acute unilateral ureteral obstruction in rats. 183 64


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