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 prevalence and development of antibodies to H+,K+-ATPase were investigated with a sensitive enzyme-linked immunosorbent assay in 86 patients with autoimmune atrophic gastritis (type A). Sixty-nine of the patients had pernicious anemia, and 17 had simple atrophic gastritis. Elevated titers were found in 93% of pernicious anemia probands. Women had higher levels than men: 3.24 versus 1.58 U/l (p = 0.002) (upper reference limit, 0.55 U/l). The antibody levels did not change over 1-4 years, but a gradual decrease in titers over decades was observed. All patients with pernicious anemia had low levels of pepsinogen A, a product of the gastric chief and mucous neck cells (median, 8.5 micrograms/l; reference range, 10-90 percentile, 64.4-195.5 micrograms/l), and elevated serum gastrin values (greater than 55 pmol/l) were found in 87%. Serum pepsinogen A, but not serum gastrin, correlated with H+,K(+)-ATPase antibody titers (r = 0.35, p = 0.01). In the 17 cases with simple atrophic gastritis, H+,K(+)-ATPase antibodies correlated inversely with fundic mucosal gland destruction. The data indicate that H+,K(+)-ATPase antibody titers reflect the immune responsiveness of a given patient as well as the antigenic amount, dependent on the degree of mucosal destruction and the duration of the disease.
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PMID:H+,K-ATPase antibodies in autoimmune gastritis: observations on the development of pernicious anemia. 184 12

The possibility that H+ might substitute for Na+ at Na+ sites of Na+,K+-ATPase was studied. Na+,K+-ATPase purified from pig kidney showed ouabain-sensitive K+-dependent ATPase activity in the absence of Na+ at acid pH (H+,K+-ATPase). The specific activity was 1.1 mumol Pi/mg/min at pH 5.7, whereas the specific activity of Na+,K+-ATPase was 14 mumol Pi/mg/min at pH 7.5. The enzyme was phosphorylated from ATP in the absence of Na+ at the acid pH. The initial rate of the phosphorylation was also accelerated at the acid pH in the absence of Na+, and the maximal rate obtained at pH 5.5 without Na+ was 9% of the rate at pH 7.0 with Na+. The phosphoenzyme was sensitive to K+ but almost insensitive to ADP. The phosphoenzyme was sensitive to hydroxylamine treatment and the alpha-subunit of the enzyme was found to be phosphorylated. H+,K+-ATPase was inhibited as effectively as Na+,K+-ATPase by N-ethylmaleimide but was less inhibited by oligomycin or dimethyl sulfoxide. These results indicate that protons have an Na+-like effect on the Na+ sites of Na+,K+-ATPase and suggest that protons can be transported by the sodium pump in place of Na+.
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PMID:Proton transport catalyzed by the sodium pump. Ouabain-sensitive ATPase activity and the phosphorylation of Na,K-ATPase in the absence of sodium ions. 242 57

The mycotoxin, cyclopiazonic acid (CPA), inhibits the Ca2+-stimulated ATPase (EC 3.6.1.38) and Ca2+ transport activity of sarcoplasmic reticulum (Goeger, D. E., Riley, R. T., Dorner, J. W., and Cole, R. J. (1988) Biochem. Pharmacol. 37, 978-981). We found that at low ATP concentrations (0.5-2 microM) the inhibition of ATPase activity was essentially complete at a CPA concentration of 6-8 nmol/mg protein, indicating stoichiometric reaction of CPA with the Ca2+-ATPase. Cyclopiazonic acid caused similar inhibition of the Ca2+-stimulated ATP hydrolysis in intact sarcoplasmic reticulum and in a purified preparation of Ca2+-ATPase. Cyclopiazonic acid also inhibited the Ca2+-dependent acetylphosphate, p-nitrophenylphosphate and carbamylphosphate hydrolysis by sarcoplasmic reticulum. ATP protected the enzyme in a competitive manner against inhibition by CPA, while a 10(5)-fold change in free Ca2+ concentration had only moderate effect on the extent of inhibition. CPA did not influence the crystallization of Ca2+-ATPase by vanadate or the reaction of fluorescein-5'-isothiocyanate with the Ca2+-ATPase, but it completely blocked at concentrations as low as 1-2 mol of CPA/mol of ATPase the fluorescence changes induced by Ca2+ and [ethylenebis(oxyethylenenitrilo)]tetraacetic acid (EGTA) in FITC-labeled sarcoplasmic reticulum and inhibited the cleavage of Ca2+-ATPase by trypsin at the T2 cleavage site in the presence of EGTA. These observations suggest that CPA interferes with the ATP-induced conformational changes related to Ca2+ transport. The effect of CPA on the sarcoplasmic reticulum Ca2+-ATPase appears to be fairly specific, since the kidney and brain Na+,K+-ATPase (EC 3.6.1.37), the gastric H+,K+-ATPase (EC 3.6.1.36), the mitochondrial F1-ATPase (EC 3.6.1.34), the Ca2+-ATPase of erythrocytes, and the Mg2+-activated ATPase of T-tubules and surface membranes of rat skeletal muscle were not inhibited by CPA, even at concentrations as high as 1000 nmol/mg protein.
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PMID:Cyclopiazonic acid is a specific inhibitor of the Ca2+-ATPase of sarcoplasmic reticulum. 253 Feb 15

In order to determine the role of divalent cations in the reaction mechanism of the H+,K+-ATPase, we have substituted calcium for magnesium, which is required by the H+,K+-ATPase for phosphorylation from ATP and from PO4. Calcium was chosen over other divalent cations assayed (barium and manganese) because in the absence of magnesium, calcium activated ATP hydrolysis, generated sufficiently high levels of phosphoenzyme (573 +/- 51 pmol.mg-1) from [gamma-32P]ATP to study dephosphorylation, and inhibited K+-stimulated ATP hydrolysis. The Ca2+-ATPase activity of the H+,K+-ATPase was 40% of the basal Mg2+-ATPase activity. However, the Ca2+,K+-ATPase activity (minus the Ca2+ basal activity) was only 0.7% of the Mg2+,K+-ATPase, indicating that calcium could partially substitute for Mg2+ in activating ATP hydrolysis but not in K+ stimulation of ATP hydrolysis. Approximately 0.1 mM calcium inhibited 50% of the Mg2+-ATPase or Mg2+,K+-ATPase activities. Inhibition of Mg2+,K+-ATPase activity was not competitive with respect to K+. Inhibition by calcium of Mg2+,K+ activity p-nitrophenyl phosphatase activity was competitive with respect to Mg2+ with an apparent Ki of 0.27 mM. Proton transport measured by acridine orange uptake was not detected in the presence of Ca2+ and K+. In the presence of Mg2+ and K+, Ca2+ inhibited proton transport with an apparent affinity similar to the inhibition of the Mg2+, K+-ATPase activity. The site of calcium inhibition was on the exterior of the vesicle. These results suggest that calcium activates basal turnover and inhibits K+ stimulation of the H+,K+-ATPase by binding at a cytosolic divalent cation site. The pseudo-first order rate constant for phosphoenzyme formation from 5 microM [gamma-32P]ATP was at least 22 times slower in the presence of calcium (0.015 s-1) than magnesium (greater than 0.310 s-1). The Ca.EP (phosphoenzyme formed in the presence of Ca2+) formed dephosphorylated four to five times more slowly that the Mg.EP (phosphoenzyme formed in the presence of Mg2+) in the presence of 8 mm trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid (CDTA) or 250 microM ATP. Approximately 10% of the Ca.EP formed was sensitive to a 100 mM KCl chase compared with greater than 85% of the Mg.EP. By comparing the transient kinetics of the phosphoenzyme formed in the presence of magnesium (Mg.EP) and calcium (Ca.EP), we found two actions of divalent cations on dephosphorylation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The substitution of calcium for magnesium in H+,K+-ATPase catalytic cycle. Evidence for two actions of divalent cations. 255 12

ALE-36, as well as omeprazole and SCH 28080, markedly inhibited the [14C]aminopyrine (AP) accumulation induced by dibutyryl cyclic AMP (dbcAMP) and H+,K+-ATPase activity in a concentration-dependent manner. The inhibitory effect of omeprazole on the dbcAMP-induced [14C]AP accumulation was reversed by treatment with beta-mercaptoethanol, but those of ALE-36 and SCH 28080 were not. ALE-36 and SCH 28080 did not inhibit dog renal Na+,K+-ATPase activity, while omeprazole and ouabain did inhibit this enzyme activity. These results suggest that the inhibitory action of ALE-36 on acid secretion is due to the specific inhibition of gastric H+,K+-ATPase, the manner being different from in the case of omeprazole.
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PMID:Inhibition of H+,K+-ATPase by methyl(E)-2-(3,4-dimethoxystyryl)-benzimidazole-4-carboxylate (ALE-36). 255 88

The mammalian parietal cell is dedicated to the secretion of HCl in response to various stimuli and second messengers. Oxidative metabolism in the cell increases about 10-fold in order to supply ATP to the gastric proton pump, the H+,K+-ATPase. This pump appears to be present only in the parietal cell. This membrane-embedded enzyme uses the scalar energy of ATP hydrolysis to carry out the vectorial transport of H+ in one direction in exchange for K+ in the other direction. In the cytoplasmic vesicle, K+ does not permeate the membrane, whereas in the secretory canaliculus, there is a Cl- channel and a KCl cotransport pathway which allow K+ and Cl- to exit from the cell. The K+ is then recycled back into the cell by the ATPase, and H+ secretion occurs into the canalicular space. Although there are other proton pumps, only the gastric H+,K+-ATPase has this exchange mechanism and only the gastric H+,K+-ATPase is able to generate a pH of less than 4. Thus the gastric proton pump has a unique structure and mechanism, and produces a unique luminal pH. This enzyme is therefore an appropriate target for rational drug design.
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PMID:The gastric H+,K+-ATPase: the site of action of omeprazole. 255 69

In cultured cells derived from isolated micromeres of sea urchin eggs, H+,K+-ATPase activity, which became detectable simultaneously with the initiation of spicule formation, was localized in the plasma membrane and the microsome fractions. Activities of marker enzymes for plasma membrane, 5'-nucleotidase, Na+,K+-ATPase, and adenylate cyclase, were found to be high in the plasma membrane fraction. Considerable activity of rotenone-insensitive NADPH-cytochrome c reductase, a marker enzyme for microsome, was detectable in the microsome fraction. These fractions exhibited barely any appreciable activity of markers for the other organellae. H+,K+-ATPase in plasma membrane probably mediates H+ release from the cells, in which H+ is produced in overall reaction to form CaCO3, the main component of spicules, from Ca2+, CO2 and H2O. Cl-,HCO3(-)-ATPase activity was also found in these two fractions before and after the initiation of spicule formation. After initiation, the skeletal vacuole fraction was obtained from subcellular structures containing spicules. Considerable activity of Cl-,HCO3(-)-ATPase was observed in this fraction, which exhibited a weak activity of UDP-galactose: N-acetylglucosamine galactosyltransferase, a marker enzyme for Golgi body. Cl-,HCO3(-)-ATPase in the skeletal vacuole membrane probably mediates HCO3- transport into the vacuoles to supply HCO3- for spicule formation.
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PMID:Distributions of H+,K+-ATPase and Cl-,HCO3(-)-ATPase in micromere-derived cells of sea urchin embryos. 283 20

A light-sensitive derivative, 2,3-dimethyl-8-[(4-azidophenyl)methoxy]imidazo[1,2-a]pyridine (DAZIP), of the drug 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine (SCH 28080) has been synthesized and shown to be a K+-competitive inhibitor of gastric H+,K+-ATPase in the dark. The apparent dissociation constants calculated for DAZIP at pH 6.4 and 7.4 were 1.8 +/- 0.2 and 4.7 +/- 1.2 microM, respectively. Inhibition required binding of DAZIP to a luminal-facing site on the enzyme. Irradiation in the presence of DAZIP and 2 mM Mg2+ resulted in irreversible loss of ATPase activity that was more than 2-fold greater at pH 6.4 than at pH 7.4, showing the enhanced efficiency of covalent incorporation at the lower pH. Further photolyses were conducted at pH 6.4 in the presence of either 1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid (CDTA), ATP and CDTA, or MgATP. The specificity of light-dependent, covalent insertion of DAZIP for the site of reversible inhibition was shown both by protection against photoinactivation given by K+ (the competing ligand) and by the observation that the amount of K+-protectable photoinactivation approached a maximum limiting value as a function of DAZIP concentration. The effectiveness of K+ in protecting against photoinactivation was 100-fold greater in the presence of ATP and CDTA than in the presence of either Mg2+ or CDTA and suggests the formation of a ternary complex of the apoenzyme with ATP and tightly bound K+. The dissociation constant for DAZIP (2 microM) calculated from photolyses in the presence of MgATP without added K+ agreed with the kinetic experiments and suggests that DAZIP inhibits turnover by binding to E.MgATP.
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PMID:Inactivation of H+,K+-ATPase by a K+-competitive photoaffinity inhibitor. 284 21

We have isolated a cDNA encoding the 31-kDa subunit of the bovine kidney vacuolar H+-ATPase. The composite sequence contains 1219 base pairs, which includes the entire 678-base-pair coding region. A lysine-rich sequence previously found in the Na+, K+-ATPase alpha subunit and the H+,K+-ATPase was identified in the 31-kDa subunit. An RNA blot and an immunoblot demonstrated variable 31-kDa subunit expression and immunoreactivity in different tissues; the highest levels were observed in kidney medulla and brain with both types of analysis. The isolation of a cDNA for the 31-kDa subunit is an important step in understanding this subunit's role in the function and regulation of the vacuolar H+-ATPase.
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PMID:Isolation and sequence of a cDNA clone encoding the 31-kDa subunit of bovine kidney vacuolar H+-ATPase. 289 53

Gastric H+,K+-ATPase activity is not affected by Na+ at pH 7.0 but is significantly stimulated by Na+ at pH 8.5. For the stimulation at the latter pH, the presence of both Na+ and K+ were essential. Contrary the H+,K+-ATPase, the associated K+-pNPPase was inhibited by Na+ at both pH values. Sodium competes with K+ for the K+-pNPPase reaction. Also, unlike the H+, K+-ATPase activity the ATPase-mediated transport of H+ within the gastric microsomal vesicles was inhibited by Na+. For the latter event only the extravesicular and not the intravesicular Na+ was effective. The data suggest that the K+-pNPPase activity does not represent the phosphatase step of the H+,K+-ATPase reaction. In addition, the observed inhibition of vesicular H+ uptake by Na+ appears to be due to the displacement by Na+ of a cytosolic (extravesicular) H+ site responsible for the vectorial translocation of H+.
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PMID:Modulation of gastric H+,K+-transporting ATPase function by sodium. 298 40


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