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)

Addition of lithium fluoride to a suspension of Na,K-ATPase undergoing turnover produced a slow (minutes) complete loss of ouabain-sensitive ATPase activity. Persistence of the effect in the presence of deferoxamine showed that fluoride inhibits independent of aluminum. The time course of onset of inhibition was adequately fit by a function corresponding to a monophasic transformation with a pseudo first-order rate constant (k(obs)). This constant varied hyperbolically with [Mg2+] (half-maximal effect at 9 mM Mg2+), whereas it increased with no sign of approaching saturation as the square of [F-], implying that inhibition requires binding of two fluorides/ATPase. The value of k(obs) was found to be increased by greater than 10-fold in the presence of potassium ([K+]1/2 = 0.6 mM) or ouabain. Sodium, ATP, and ADP, which favor the E1 form of the enzyme, had a protective effect. These results implicate the potassium-occluded MgE2(K2) complex as the main fluoride-susceptible form. Protection by Pi and orthovanadate suggests that fluoride exerts its effect at the phosphorylation site. Inhibition was reversible, although slowly, with t1/2 = 7 h at 37 degrees C. Sodium greatly accelerated reversal (t1/2 = 3 min with 150 mM Na+ present), and potassium antagonized this acceleration. The value of k(obs) for reactivation increased steeply with [Na+], with the sodium dependence being about the same at pH 8.0 as at pH 7.4. All of these effects have parallels to effects of fluoride on the sarcoplasmic reticulum CaATPase (Murphy, A. J., and Coll, R. J. (1992) J. Biol. Chem. 267, 5229-5235).
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PMID:Inhibition of the Na,K-ATPase by fluoride. Parallels with its inhibition of the sarcoplasmic reticulum CaATPase. 132 18

Beryllium and aluminum fluorides are good phosphate analogues. These compounds, like orthovanadate, form stable complexes with myosin subfragment 1 (S1) in the presence of MgADP. The formation of the stable S1-nucleotide complexes is characterized by the loss of ATPase activity. For the complete loss of ATPase activity there was necessary a higher concentration of aluminum than of beryllium or vanadate. In the presence of MgATP the onset of the inhibition is delayed, which indicates that stable complexes cannot form when a specific site is occupied by the gamma-phosphate of ATP or by P(i) derived from the gamma-phosphate. The half-lives of the S1-MgADP-(BeF3-), S1-MgADP-(AlF4-), and S1-MgADP-Vi complexes at 0 degrees C are 7, 2, and 4 days, respectively. In the presence of actin the rate of decomposition of all of the complexes is significantly enhanced; however, the order of decomposition is reversed, the fastest rate being observed with beryllium and the slowest with aluminum. The formation of the S1-MgADP-(BeF3-) and S1-MgADP-(AlF4-) complexes is accompanied by an increase in tryptophan fluorescence similar to that observed upon addition of MgATP to S1. The fluorescence increase develops rather slowly, by suggesting that the rate-limiting step in the formation of the stable complex is an isomerization. The rate of the fluorescence change accompanying the formation of the Be complex is faster than that for the Al complex. Addition of vanadate to S1 causes a static quenching of the tryptophan fluorescence.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of stable beryllium fluoride, aluminum fluoride, and vanadate containing myosin subfragment 1-nucleotide complexes. 138 27

Addition of sodium fluoride in the millimolar concentration range to a solution containing the sarcoplasmic reticulum CaATPase undergoing turnover in its vesicular or nonionic detergent-solubilized forms produced a slow (time range of minutes) complete loss of enzymatic activity. In the presence of magnesium and the absence of calcium, similar results were obtained under nonturnover conditions. Time courses were adequately fit by a function corresponding to a monophasic transformation with a pseudo first order rate constant kobs. In the absence of Mg2+ (EDTA present) no inhibition developed; kobs depended hyperbolically on the Mg2+ concentration with the half maximal effect occurring near 4 mM. The fluoride concentration dependence of kobs showed no evidence of approaching saturation (highest [F-] used was 40 mM) and corresponded to a rate law which was approximately second-order with respect to fluoride. A number of ligands known to bind to the CaATPase were found to decrease kobs. Calcium prevented onset of fluoride inhibition with a midpoint in the micromolar range, implying an effect due to binding at the high affinity transport sites. ATP also protected with a midpoint in the micromolar range, consistent with an effect caused by active site binding of the nucleotide; protection was only partial, suggesting the ATPase can bind fluoride and ATP simultaneously. Prevention of fluoride inhibition by Pi occurred with a [Pi]1/2 of 12 mM at pH 6.5, a concentration similar to that which produces active site phosphorylation. Finally, protection by orthovanadate was found to be competitive and have a midpoint of 5 microM. These results point to an effect exerted at or near the phosphorylation site. The value of kobs increased from essentially zero above pH 8 to a plateau below pH 6; the transition had a midpoint near pH 7.2. Inhibition persisted after removal (with EGTA present) of unbound fluoride by dialysis. Reversal of fluoride inhibition was very slow, with a t1/2 of 16 h at 37 degrees C. These results suggest that fluoride behaves like a slow, tight-binding inhibitor of the ATPase and that the resulting complex is a stable transition (or intermediate) state analog. Plausible molecular bases for our results are that fluoride acts at the phosphorylation site as an analog of Pi or of hydroxide, which may be considered a substrate in the normal hydrolysis of the phosphorylated enzyme. A role for aluminum was ruled out after finding that the addition of EGTA to 10 mM or aluminum sulfate to 0.2 mM or deferoxamine to 0.5 mM produced no significant change in kobs.
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PMID:Fluoride is a slow, tight-binding inhibitor of the calcium ATPase of sarcoplasmic reticulum. 153 81

The vanadate-sensitive Mg(2+)-dependent ATPase activity of the human erythrocyte ghost is believed to be involved in the shape change events that convert echinocytic ghosts to smoothed forms (biconcave discs and stomatocytes). At physiological salt concentration, pH 7.4, 2 mM ATP, 5 mM Mg2+ and 1 mM EGTA, the Mg(2+)-ATPase activity of ghosts was inhibited strongly by millimolar concentrations of sodium fluoride: I50 = 1.31 +/- 0.23 mM (mean +/- S.D.; n = 12). The addition of aluminium chloride to 15 microM reduced the concentration of NaF required for 50% inhibition to 0.76 +/- 0.21 mM (n = 10). Aluminium alone had only a small inhibitory effect on the ATPase activity (13 +/- 9%; n = 10). Desferrioxamine, a strong chelator of tervalent aluminium ion, failed to reverse the inhibition by fluoride and reversed the inhibition in the presence of aluminium and fluoride back to those values obtained with fluoride alone. Of several metal salts tested only beryllium sulfate was able to replace aluminium as an effective inhibitor in the presence of fluoride. Inhibition of the Mg(2+)-ATPase activity by fluoride and the aluminofluoride complexes correlated with an inhibition of the rate of MgATP-dependent change in red cell ghost shape from echinocytes to smoothed forms. All gross morphological changes of the smoothing process were affected, including the production of discocytes, stomatocytes and endocyctic vesicles.
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PMID:The inhibition of ATP-dependent shape change of human erythrocyte ghosts correlates with an inhibition of Mg(2+)-ATPase activity by fluoride and aluminofluoride complexes. 153 44

1. Membrane fractions were obtained from homogenates of olfactory rosettes from Atlantic salmon (Salmo salar) or from isolated olfactory cilia and homogenates of deciliated olfactory rosettes. 2. Specific binding of L-[3H]alanine was saturable, high-affinity, and effectively inhibited by L-threonine, L-serine and L-alanine but not by L-lysine or L-glutamic acid. Comparable results were obtained with L-[3H]serine except for the presence of a second, lower affinity, binding site for L-alanine but not L-serine. 3. Specific binding of L-[3H]alanine was inhibited by low concentrations of mercury ion, acidic pH, and high concentrations of cadmium, copper or zinc ions. Aluminum had no effect. 4. Specific binding sites for L-alanine were present in membranes from isolated cilia at a level 2-fold that of membranes prepared from the deciliated rosette. 5. Ouabain sensitive Na+, K(+)-ATPase activity was also determined in cilia preparations. This enzyme was present in cilia at a level approximately 3-fold that of membranes prepared from the deciliated rosette. 6. The results are consistent with the presence of an olfactory alanine receptor in S. salar with binding characteristics similar to those of a variety of other fish species and with a localization on olfactory cilia as well as non-ciliated receptor cell membranes.
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PMID:L-alanine binding sites and Na+, K(+)-ATPase in cilia and other membrane fractions from olfactory rosettes of Atlantic salmon. 164 34

Diabetics have an increased risk of developing renal insufficiency, as well as congestive heart failure independent of coronary atherosclerotic or hypertensive heart disease. Aluminum toxicity is being recognized with increased frequency in patients with reduced renal function and aluminum accumulates to a greater degree in tissues of patients with diabetes. Studies in patients with end stage renal disease have implicated aluminum overload as a potential cause of reduced cardiac function. Since both diabetes and aluminum decrease the activity of (Ca + Mg)-ATPase, a key enzyme involved in myocardial calcium transport, the interaction of experimental diabetes mellitus and aluminum toxicity on myocardial sarcoplasmic reticulum calcium transport was investigated in rats. Aluminum alone had no effect on (Ca + Mg)-ATPase activity, while activities in both the diabetic ([DM]) and diabetic plus aluminum loaded ([DM + Al]) groups were significantly lower than controls ([C]). Oxalate-dependent calcium uptake in the [DM] rats was slightly, but not significantly lower than controls, however, uptake was markedly reduced in rats which were both diabetic and aluminum loaded. The calcium regulatory protein calmodulin was measured by a functional assay in the soluble fraction of myocardial tissue prepared from each of the four groups. Compared to [C], calmodulin activity was significantly reduced in both the [DM] and [DM + Al] groups but not affected by aluminum alone. These data indicate that diabetes mellitus is associated with decreased myocardial calmodulin activity that may contribute to reduced sarcoplasmic reticulum (Ca + Mg)-ATPase and calcium transport activities and that aluminium toxicity potentiates the adverse effects of diabetes on decreasing sarcoplasmic reticulum calcium uptake.
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PMID:Effects of diabetes mellitus and aluminum toxicity on myocardial calcium transport. 214 51

Complexes formed from A13+ or Be2+ and fluoride inhibit the single-stranded DNA-dependent ATPase activity of RecA protein. In contrast, poly(dT)-RecA-ADP complexes, which are inactive for cleavage of LexA protein, become fully active in the presence of AlF4- or BeF3- ions. These data suggest that fluoride complexes of aluminum and beryllium (called herein X) convert RecA-ADP complexes, which bind weakly to single-stranded DNA, into RecA-ADP-X complexes, which bind tightly to single-stranded DNA, the ADP-X moiety behaving as a nonhydrolyzable analogue of ATP. We propose that AlF4- and BeF3- ions act as analogues of inorganic phosphate by binding to the site of the gamma-phosphate of ATP on RecA-ADP complexes, hence mimicking the single-stranded DNA-RecA-ADP-Pi transition state. We conclude that the elementary reaction that switches RecA protein from a high affinity single-stranded DNA binding state to a low affinity single-stranded DNA binding state is not ATP hydrolysis per se but Pi release.
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PMID:RecA protein-promoted cleavage of LexA repressor in the presence of ADP and structural analogues of inorganic phosphate, the fluoride complexes of aluminum and beryllium. 252 26

Inhibition of the mitochondrial and bacterial F1-type ATPases [of ATP phosphohydrolase (H+-transporting), EC 3.6.1.34] by fluoride was found to depend on the presence of aluminum and ADP at the catalytic site(s) of F1-type ATPase. AIF-4 was demonstrated to be the active fluoroaluminate species. The identical pattern of inhibition of F1-type ATPase activity obtained in the presence of ADP and NaF with beryllium, a metal that forms fluoride complexes strictly tetracoordinated, suggests that aluminum acts through a tetrahedral complex. Inhibition of isolated F1-type ATPase by AIF-4 in the presence of ADP cannot be reversed by ADP, ATP, or chelators of aluminum. However, the inhibition of the ATPase activity of the F1 sector in submitochondrial particles caused by AIF-4 and ADP was reversed upon addition of an oxidizable substrate. Uncouplers prevented the reversal of inhibition, suggesting that the protonmotive force generated by respiration was responsible for the relief of inhibition. Because of structural similarities between AIF4- and , AIF4- is postulated to mimic the phosphate group of ATP and form an abortive complex with ADP at the active site(s) of F1-type ATPase.
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PMID:Inhibition of H+-transporting ATPase by formation of a tight nucleoside diphosphate-fluoroaluminate complex at the catalytic site. 290 48

Fluoride irreversibly inhibits the (Na + K)-ATPase, and this inactivation requires divalent cations (Mg2+, Mn2+, or Ca2+), is augmented by K+, but is diminished by Na+ and by ATP. Prior incubation with the aluminum chelator deferoxamine markedly slows inactivation, whereas adding 1 microM AlCl3 speeds it, consistent with AlF-4 being the active species. Prior incubation of the enzyme with vanadate also blocks inactivation by fluoride added subsequently. Fluoride stimulates ouabain binding to the enzyme, and thus the analogy between AlF-4 and both orthophosphate and orthovanadate is reflected not only in the similar dependence on specific ligands for their enzyme interactions and their apparent competition for the same sites, but also in their common ability to promote ouabain binding. Beryllium also irreversibly inhibits the enzyme, and this inactivation again requires divalent cations, is augmented by K+, but is diminished by Na+ and by ATP. Similarly, prior incubation of the enzyme with vanadate blocks inactivation by beryllium added subsequently. Inactivation by beryllium, however, does not require a halide, and, unlike inactivation by fluoride, increases at basic pHs. These observations suggest that beryllium, as beryllium hydroxide complexes, acts as a phosphate analog, similar to AlF-4 and vanadate.
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PMID:Fluoride and beryllium interact with the (Na + K)-dependent ATPase as analogs of phosphate. 302 94

The isolated rat jejunal slice was used to determine if aluminum (Al) interacts with the gastrointestinal (GI) calcium (Ca) transporting system. Al uptake by the rat jejunal slice was reduced by Ca channel blockers (verapamil, nifedipine, diltiazem-10 microM) and a medium containing no added Ca. Conversely, Al uptake was increased by Ca channel activators (4-aminopyridine, .05mM, .1mM; Bay k 8644, 1, 10 microM) and by 5mM Ca. Al uptake was saturable and energy dependent but yielded a low activation energy (Ea = 3.9 +/- 0.3 kcal/mole). Al uptake was increased by vanadate (100 microM), an inhibitor of both the active Ca pump and Na/K-ATPase. These results suggest that Al does interact with the GI Ca transporting system. This interaction may form the basis for its accumulation and toxicity in different tissues which contain similar processes for handling Ca.
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PMID:Influence of calcium on aluminum accumulation by the rat jejunal slice. 335 81


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