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)

Diethylstilbestrol is a potent inhibitory agent of the Ca(2+)-ATPase activity of sarcoplasmic reticulum membranes. Other structurally related molecules, such as dienestrol or hexestrol having hydroxyl groups at para positions of the two benzene rings produce similar effects. The absence or derivatization of the hydroxyl groups as occurs with trans-stilbene or diethylstilbestrol dipropionate converts the structure in an activating agent of the enzyme. The Ca2+ transport profiles in the presence of the referred drugs reproduces the same behavior observed for the hydrolytic activity. There is also a clear indication of a membrane-mediated mechanism of these drugs. Ligand binding experiments at equilibrium indicate that diethylstilbestrol decreases the affinity for Ca2+ of the high affinity Ca2+ sites. Functional studies reveal that the activation/inhibition induced by these drugs is correlated with decreased levels of phosphoenzyme at steady state, and these levels are sensitive to the Ca2+ concentration. Chase experiments of [32P]phosphoenzyme and 45Ca2+ indicate a slight activation effect of diethylstilbestrol dipropionate on Ca2+ dissociation during the enzyme turnover. The use of different anthroyloxy derivatives of stearic acid as a fluorescent probe suggest that diethylstilbestrol and other inhibitory agents could be located close to the polar region of the lipid bilayer, which interferes with the Ca(2+)-binding sites, whereas the activators trans-stilbene and diethylstilbestrol dipropionate may have a deeper position into the membrane, which accelerates the Ca2+ translocation process.
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PMID:Effect of diethylstilbestrol and related compounds on the Ca(2+)-transporting ATPase of sarcoplasmic reticulum. 131 6

Physiological concentrations of retinoic acid can block the activation of human erythrocyte Ca(2+)-ATPase in vitro by thyroid hormone [Smith, Davis & Davis (1989) J. Biol. Chem. 264, 687-689]. The present studies were undertaken to ascertain the nature of this blockade. Two binding sites for L-thyroxine (T4) were demonstrated on washed erythrocyte membranes; the high-affinity site had a Kd value of 2.7 x 10(-10)M and a Bmax. of 76 fmol/mg of protein. The lower-affinity site possessed a Kd of 1 x 10(-8) M. Retinoic acid was as potent a displacer of radiolabelled T4 as was the unlabelled hormone. Certain retinoic acid analogues with either ring or fatty acid side chain modifications retained some ability to displace [125I]T4 binding and to block iodothyronine activation of Ca(2+)-ATPase. The side chain terminal carboxyl group was essential for full activity of the retinoic acid molecule. Its absence or replacement with an ethylsulphone group rendered the molecule considerably less active in the ATPase model. Retinol, 13-cis-retinoic acid, benzene-substituted all-trans-retinoic acid and polyprenoic acid all failed to influence iodothyronine binding or to block activation of Ca(2+)-ATPase by T4. There was good agreement between the ability of an analogue to displace [125I]iodothyronine binding and its ability to inhibit the T4-dependent activation of the Ca(2+)-ATPase. It would appear from these observations that retinoic acid can modulate the activation of erythrocyte membrane Ca(2+)-ATPase by thyroid hormone through a mechanism which involves displacement of iodothyronine from binding sites. These activities apparently derive from both the ring structure and the fatty acid side chain of the retinoic acid molecule.
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PMID:Stereochemical requirements for the modulation by retinoic acid of thyroid hormone activation of Ca(2+)-ATPase and binding at the human erythrocyte membrane. 153 54

Resorcinolic lipids, amphiphilic compounds from cereal grains show strong effects upon the activity of membrane enzymes. The concentrations for 50% inhibition of erythrocyte membrane acetylcholinesterase were in the range of 18-90 microM and were dependent on the length of the aliphatic side chain of the homologue and on the modification of hydroxyl groups in the benzene ring. Sulfonation of OH groups resulted in a drastic decrease of the inhibitory potency. The effect of resorcinolic lipids on the activity of Ca2+(calmodulin)-ATPase was the opposite. Up to concentrations of 50 microM alk(en)ylresorcinols stimulated the activity of this enzyme and only slight inhibition (approx. 30%) was observed above 100 microM. The results suggest that the effect of resorcinolic lipids might depend on their ability to alter the bilayer properties. Most probably these compounds decrease the mobility of membrane phospholipid molecules.
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PMID:Modulation of the activities of membrane enzymes by cereal grain resorcinolic lipids. 161 Apr 78

All-trans retinoic acid displaces the binding of radiolabelled calmodulin to human erythrocyte membranes, and inhibits the activity of plasma membrane Ca(2+)-stimulated, Mg(2+)-dependent ATPase (Ca(2+)-ATPase; EC 3.6.1.3). This enzyme is dependent upon the action of calmodulin. In this study we explored the structural attributes of the retinoids which confer this ability to inhibit enzyme activity and calmodulin binding. With respect to the fatty acid side-chain, a clear requirement for inhibition is a trans-configuration of the polar end-group. The importance of the ring structure is indicated by the ineffectiveness of polyprenoic acid and a benzene ring retinoid analogue as inhibitors of enzyme activity and calmodulin binding. There was good correlation between the relative potencies of the analogues as enzyme inhibitors and as inhibitors of calmodulin binding. The ability of selected retinoid analogues, at physiological concentrations with respect to all-trans retinoic acid, to inhibit erythrocyte Ca(2+)-ATPase activity and membrane binding of calmodulin underscores the structurally specific effects of these compounds on the interaction of calmodulin with the membrane-bound enzyme.
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PMID:Structure-activity relationships of retinoids as inhibitors of calmodulin-dependent human erythrocyte Ca(2+)-ATPase activity and calmodulin binding to membranes. 183 50

The Diels-Alder reactions of a cardiac glycoside, proscillaridin (1), with some dienophiles were investigated. The reaction of 1 with alkenes such as methyl vinyl ketone and methyl acrylate afforded 3-oxo-2-oxabicyclo[2.2.2]oct-7-enes (2-5) and para-substituted benzene derivatives (6 and 7), while 1 reacted with alkynes (3-butyn-2-one, methyl propiolate) to yield para- or meta-substituted benzene derivatives (6-9). The biological activities of the resulting derivatives were evaluated by the use of isolated guinea-pig papillary muscle preparations and Na+,K(+)-adenosine triphosphatase (ATPase) preparation from dog kidney. Among the proscillaridin derivatives, compounds 4 and 7 moderately inhibited Na+,K(+)-ATPase activity. Furthermore, the concentration range of 7 over which its positive inotropic effect on guinea-pig papillary muscle preparations, increased from 5% to 95% of maximum was broader than that of 1, i.e., concentration dependency was maintained over a greater range of concentration.
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PMID:Studies on cardiac ingredients of plants. VII: Chemical transformation of proscillaridin by means of the Diels-Alder reaction and biological activities of its derivatives. 183 42

Purified gastric (H(+)+K+)-transporting ATPase [(H(+)+K+)-ATPase] from the parietal cells always contains a certain amount of basal Mg2(+)-dependent ATPase (Mg2(+)-ATPase) activity. lin-Benzo-ATP (the prefix lin refers to the linear disposition of the pyrimidine, benzene and imidazole rings in the 'stretched-out' version of the adenine nucleus), an ATP analogue with a benzene ring formally inserted between the two rings composing the adenosine moiety, is an interesting substrate not only because of its fluorescent behaviour, but also because of its geometric properties. lin-Benzo-ATP was used in the present study to elucidate the possible role of the basal Mg2(+)-ATPase activity in the gastric (H(+)+K+)-ATPase preparation. With lin-benzo-ATP the enzyme can be phosphorylated such that a conventional phosphoenzyme intermediate is formed. The rate of the phosphorylation reaction, however, is so low that this reaction with subsequent dephosphorylation cannot account for the much higher rate of hydrolysis of lin-benzo-ATP by the enzyme. This apparent kinetic discrepancy indicates that lin-benzo-ATP is not a substrate for the (H(+)+K+)-ATPase reaction cycle. This idea was further supported by the finding that lin-benzo-ATP was unable to catalyse H+ uptake by gastric-mucosa vesicles. The breakdown of lin-benzo-ATP by the (H(+)+K+)-ATPase preparation must be due to a hydrolytic activity which is not involved in the ion-transporting reaction cycle of the (H(+)+K+)-ATPase itself. Comparison of the basal Mg2(+)-ATPase activity (with ATP as substrate) with the hydrolytic activity of (H(+)+K+)-ATPase using lin-benzo-ATP as substrate and the effect of the inhibitors omeprazole and SCH 28080 support the notion that lin-benzo-ATP is not hydrolysed by the (H(+)+K+)-ATPase, but by the basal Mg2(+)-ATPase, and that the activity of the latter enzyme is not involved in the (H(+)+K+)-transporting reaction cycle (according to the Albers-Post formalism) of (H(+)+K+)-ATPase.
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PMID:The basal Mg2(+)-dependent ATPase activity is not part of the (H(+)+K+)-transporting ATPase reaction cycle. 216 Feb 31

Ca2(+)-ATPase activity in human red cell membranes is dependent on the presence of calmodulin. All trans-retinoic acid inhibited human red cell membrane Ca2(+)-ATPase activity in vitro in a concentration-dependent manner (10(-8) to 10(-4) M). In contrast, retinol, retinal, 13-cis-retinoic acid and the benzene ring analogue of retinoic acid did not alter enzyme activity. Purified calmodulin (up to 500 ng/ml, 3 X 10(-8) M) added to red cell membranes, in the presence of inhibitory concentrations of retinoic acid, only partially restored Ca2(+)-ATPase activity. 125I-Calmodulin bound to red cell membranes was displaced by unlabeled retinoic acid (50% reduction at 10(-8) M retinoic acid), as effectively as by unlabeled calmodulin. Another calmodulin-stimulable enzyme, bovine brain cyclic nucleotide phosphodiesterase, was unaffected by retinoic acid. 8-Anilino-1-naphthalene sulfonic acid bound to calmodulin, studied spectrofluorometrically, was not displaced by retinoic acid. Thus, retinoic acid inhibits calmodulin binding to red cell membranes, reducing calmodulin-stimulable Ca2(+)-ATPase activity. Retinoic acid does not directly interact with calmodulin, but rather exerts its effect by interfering with calmodulin access to the membrane enzyme. These effects occur at physiological concentrations of the retinoid.
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PMID:Retinoic acid inhibits calmodulin binding to human erythrocyte membranes and reduces membrane Ca2(+)-adenosine triphosphatase activity. 216 34

(Na+,K+)ATPase activity of rat liver plasma membranes was evaluated in female rats feeding an ethanol containing diet for 46 days (total ethanol ingested, 59.7 g/100 g body wt). Determinations were performed at the end of ethanol treatment or at various times after stopping treatment. (Na+,K+)ATPase and 5'-nucleotidase activities exhibited a 8- and 1.4-fold decrease, respectively, at the end of ethanol ingestion. In contrast no modifications of Mg2+-ATPase activity were observed. There also occurred, in ethanol-treated rats, release of sorbitol dehydrogenase into the blood, fat accumulation in liver cells, and decrease in reduced glutathione (GSH) liver content. A decrease in (Na+,K+)ATPase activity was also found in plasma membranes isolated from hepatocyte suspensions after a 2-hr incubation with 50 mM ethanol or 1 mM acetaldehyde (ACA), in conditions that caused a great fall in hepatocyte GSH content but did not cause cell death. After the cessation of ethanol administration, there occurred a progressive recovery of (Na+,K+)ATPase activity, GSH and triacylglycerol content, and release of sorbitol dehydrogenase. These parameters reached control values 12 hr after ethanol withdrawal. S-Adenosyl-L-methionine (SAM), L-methionine, and N-acetylcysteine (NAC), given to rats during ethanol treatment, prevented the decrease in (Na+,K+)ATPase activity and GSH content. They also reduced steatosis and liver necrosis. The efficiency of these compounds decreased in this order: SAM, methionine, NAC. SAM accelerated the recovery of all parameters studied after ethanol withdrawal, and also protected (Na+,K+)ATPase activity and GSH content of isolated hepatocytes from the deleterious effect of ethanol. These SAM effects were prevented by 1-chloro-2,4-dinitro-benzene, a compound which depletes cell GSH. Treatment of isolated hepatocytes with [35S]SAM led to the synthesis of labeled GSH. The total amount and specific activity of labeled GSH underwent a significant increase, in the presence of 2 mM ethanol or 0.5 mM ACA, which indicates a marked stimulation of GSH synthesis by ethanol and ACA. These data indicate that ethanol intoxication may inhibit (Na+,K+)ATPase activity; an effect that does not seem to depend on cell necrosis. SAM, methionine, and NAC exert various degrees of protection toward ethanol-induced cell injury, which are related to the efficiency of these compounds in maintaining a high GSH pool.
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PMID:Inhibition by ethanol of rat liver plasma membrane (Na+,K+)ATPase: protective effect of S-adenosyl-L-methionine, L-methionine, and N-acetylcysteine. 253 5

The F0 portion of the rat liver mitochondrial ATP synthase (F0F1-ATPase) has been purified by a rapid, high yield procedure. F0 is selectively extracted from inner membrane vesicles with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) after prior treatment of the vesicles with guanidine HCl to remove F1. The resultant F0 is functional in proton translocation assays and separates in sodium dodecyl sulfate-polyacrylamide gel electrophoresis into four major and three minor Coomassie-stainable bands, all with apparent molecular masses below 30 kDa. This CHAPS-purified F0 preparation was characterized in detail for its capacity to interact with the unique probe diethylstilbestrol (DES) which, depending on conditions, has been shown to interact with rat liver F0F1 to either inhibit or promote ATP hydrolysis (McEnery, M. W., and Pedersen, P.L. (1986) J. Biol. Chem. 261, 1745-1752). DES-inhibitory sensitivity could be conferred on F1-ATPase activity with the same concentration dependence on F0 as conferral of oligomycin sensitivity. DES was shown also to inhibit the magnitude of valinomycin induced proton influx, while initiating proton efflux in asolectin vesicles reconstituted with F0 and loaded with K+. The potency of DES in producing the latter effects was shown to be highly dependent on hydroxyl groups in "para" positions of the two benzene rings within the DES molecule. Finally, in the absence of F0, DES was shown to act as a catalyst of proton influx in K+-loaded asolectin vesicles upon addition of valinomycin. A model based on the structure of DES is presented to account for both the inhibitory and uncoupling properties of this compound.
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PMID:F0 "proton channel" of rat liver mitochondria. Rapid purification of a functional complex and a study of its interaction with the unique probe diethylstilbestrol. 254 97

Retinal pigment epithelium plasma membranes have been isolated by differential and density gradient centrifugation of glass-bead-bound, collagenase-treated cells. Electron microscopic evidence indicates that the glass-bead-bound cells were devoid of red blood cells, rod outer segments and other ocular cell contaminants. The plasma membranes were recovered in 4-6 micrograms/eye yields and purified 10-fold by 5'-nucleotidase and alkaline phosphodiesterase I, and 6.5-fold by (Na+ + K+)-ATPase. Plasma membrane purity as measured by covalent labeling of the epithelial cell plasma membrane proteins with p-(diazonium) benzene[32S]sulfonic acid was 8-19-fold. In purified plasma membranes contamination by mitochondria was undetectable and lysosomal contamination reduced 100-fold, while endoplasmic reticulum was 2-fold enriched. SDS-polyacrylamide gel electrophoresis of the plasma membrane proteins revealed 23-26 major bands by Coomassie blue staining and 12-16 major bands by radioactive labeling. The plasma membranes exhibited a 3-fold lower concentration of docosahexaenoic acid, a 3-fold higher cholesterol/phosphate ratio, and were 10-fold enriched in cholesterol per micrograms protein when compared to the whole cell fraction. Retinal epithelial plasma membranes contain an average of 1 mol cholesterol per mol of lipid phosphorus, a high palmitic acid concentration (39 mol%) and a low concentration of docosahexaenoic acid (2 mol%). The lipid profile of the retinal pigment epithelial plasma membranes indicates that they are typical of plasma membranes from many other cell types and that they appear to be less fluid than total rod outer segment membranes.
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PMID:Isolation of plasma membranes from the bovine retinal pigment epithelium. 298 2


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