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)

Injury to the gastric mucosa associated with the use of aspirin and other NSAIDs appears to be principally attributable to impairment of mucosal defense mechanisms against damage by acid and pepsin, that are mediated largely by prostaglandins. Modification of the drug dose or delivery system and substitution of a less gastrotoxic agent, such as a nonacetylated salicylate, are among the initial approaches that have been used to reduce the risk of NSAID-induced gastric injury. Other recommended measures include the avoidance of cigarettes, concentrated alcohol, and combination therapy with multiple NSAIDs. In high-risk patients, especially those with previous peptic ulcer disease, prophylactic therapy with a cytoprotective or acid-secretion-reducing drug is indicated. Drugs often used in the treatment of NSAID-associated mucosal damage include H2-receptor blockers, which inhibit gastric acid secretion, and agents such as synthetic prostaglandins and sucralfate, which improve mucosal defense. More potent inhibitors of gastric acid, such as drugs which block H+/K+ ATPase, may offer improved results for healing NSAID-induced gastric ulcers resistant to other therapy. Because NSAID-induced gastric lesions are not always accompanied by symptoms, patients receiving these drugs must be closely monitored for signs of gastric injury. Small ulcers can generally be healed with antiulcer medications. In patients with larger ulcers, withdrawal of NSAID therapy is usually required, at least until healing has occurred.
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PMID:NSAID-induced gastric injury: its pathogenesis and management. 218 75

Monoclonal antibodies directed against epitopes on each of the five subunits (alpha, beta, gamma, delta, and epsilon) of the Escherichia coli F1 ATPase (ECF1) have been prepared and used to localize the subunits in the enzyme complex. Fab' fragments, prepared by pepsin digestion of the antibodies, were bound to ECF1 and visualized by cryoelectron microscopy of the unstained, frozen hydrated ECF1-Fab' complexes. Besides aiding in the identification of the ECF1 subunits, addition of Fab's to the specimen fortuitously offers additional advantages in this technique. ECF1 labeled with anti-alpha Fab' is uniformly oriented in the amorphous ice layer, in contrast to unlabeled ECF1, which exhibits a multitude of projection views when examined in ice. Almost all complexes display a triangular projection, which image averaging reveals to be a hexagonal view of ECF1 with Fab' fragments labeling every other peripheral subunit, confirming the alternating arrangement of alpha and beta subunits in the enzyme. A density in the interior of the structure is positioned asymmetrically, adjacent to an unlabeled peripheral mass, indicating that its primary linkage is to a beta rather than an alpha subunit. The composition of the asymmetric density was explored by examining the trypsin-treated ECF1, taking advantage of the unique orientation induced by the binding of anti-alpha Fab'. Trypsin treatment releases the delta and epsilon subunits and cleaves the gamma subunit; the internal density is reduced but not eliminated, showing the contribution of the gamma subunit to the residual structure, and suggesting that the loss of the delta and epsilon subunits, or a structural rearrangement of the gamma subunit, is responsible for its smaller size.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cryoelectron microscopy of Escherichia coli F1 adenosinetriphosphatase decorated with monoclonal antibodies to individual subunits of the complex. 247 70

Using isolated cells and subcellular fractions from pig gastric mucosa, antigenic structures with specific binding of IgG from sera of patients with auto-immune atrophic gastritis were characterized by means of immunoblotting and enzyme-linked immunosorbent assay. In immunoblotting experiments using mucosal cells as the antigen source, two dominating bands of 94 and 41 kDa were found. The two major antigens were identified as the H,K-ATPase (94 kDa), which constitutes the parietal cell acid pump, and pepsinogen (41 kDa) located in the chief cells. There was also a small but significant binding of antibodies to a preparation of Na,K-ATPase, an enzyme which is about 60% homologous to H,K-ATPase. Commercial preparations of hog gastric pepsinogen and pepsin bound pernicious anaemia IgG with equal efficacy. When sera from seven patients with the diagnosis pernicious anaemia were tested, all were found to contain auto-antibodies against H,K-ATPase as well as pepsinogen. In intact, isolated H,K-ATPase-containing vesicles the cytosolic part of the ATPase molecule is facing the outside of the vesicles. Both intact and trypsinized vesicles were incubated with patient sera and with a monoclonal antibody against H,K-ATPase. Pernicious anaemia IgG was found to bind to a cytosolic, trypsin-resistant structure, but the binding of the monoclonal antibody was lost upon trypsinization. The present results indicate that intracellular structures of the gastric mucosa, due to cell damage, may be exposed to immune-competent cells, which do not recognize these structures as 'self'.
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PMID:Characterization of antigenic structures in auto-immune atrophic gastritis with pernicious anaemia. The parietal cell H,K-ATPase and the chief cell pepsinogen are the two major antigens. 252 90

Omeprazole, a potent inhibitor of gastric hydrogen ion transporting, potassium-stimulated adenosine triphosphatase, was found to be transformed into an SH-reactive strong fluorescent molecule (excitation and emission wavelengths of 370 and 560 nm, respectively) in an acidic medium. The addition of glutathione- or protein-containing sulfhydryl groups such as pepsin to the medium decreased the fluorescence. Also, the increase in the pH of the medium decreased the fluorescence. The fluorescent molecule was identified to be an acid-activated planar cyclic sulfenamide derivative of omeprazole. The transformation was studied in H+-preaccumulated hog gastric vesicles, which contain the hydrogen ion transporting, potassium-stimulated adenosine triphosphatase. The addition of omeprazole to the vesicle suspension induced a rapid increase in the fluorescence intensity, indicating that omeprazole was activated in the intravesicular space. Then, the intensity biphasically decreased with time. The slower small decrease was due to the reaction of the sulfenamide with sulfhydryl group(s) located on the acid secretory side of the hydrogen ion transporting, potassium-stimulated adenosine triphosphatase. Omeprazole was also activated in the acidic lumina of isolated rabbit gastric glands that were stimulated with histamine. Furthermore, direct evidence was obtained from the imaging of the fluorescence that omeprazole was activated in the acidic compartments of the isolated Xenopus oxyntic cell.
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PMID:Acid activation of omeprazole in isolated gastric vesicles, oxyntic cells, and gastric glands. 254 Oct 41

Omeprazole is the first H+-K+-adenosine triphosphatase antagonist available for clinical use. It has a very strong, long-lasting inhibitory effect on gastric acid secretion. The effect is very selective: pepsin and intrinsic factor secretion are unaffected. Once-daily doses of 30-40 mg cause a more than 95% reduction of intragastric acidity. Lower doses have less predictable results. During treatment with omeprazole serum gastrin levels increase. After cessation of treatment gastric acid secretion and serum gastrin levels rapidly return to pretreatment levels. No rebound phenomena are observed after treatment.
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PMID:Effects of omeprazole on gastric secretory functions. 269 7

The results reported in this paper indicate that representative H2-receptor antagonists are capable of maximally inhibiting gastric acid secretion in animals under the two general circumstances in which it occurs physiologically. Interdigestive or basal secretion was examined in chronic gastric fistula rats and food-stimulated secretion in vagally innervated, lesser curvature pouch dogs. The H2 antagonists studied and omeprazole, an inhibitor of the proton pump H+, K+-adenosine triphosphatase, also decreased pepsin secretion in rats, although not to the same maximal degree as acid secretion. Gastric emptying was increased by each H2 antagonist but only at high acid inhibitory doses. Omeprazole, in contrast, did not alter gastric emptying at a similar antisecretory dosage level. In dogs, a representative H2-receptor antagonist markedly inhibited food-stimulated acid secretion. These data suggest that the predominant effect of omeprazole and H2-receptor antagonists upon gastric function is to inhibit acid secretion and that H2-receptor antagonists may be capable of maximally inhibiting endogenous acid secretion in humans, as does omeprazole, if given under proper conditions.
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PMID:Effects of H2-receptor antagonists upon physiological acid secretory states in animals. 285 83

Two geometric isomers of covalently labeled F1-adenosinetriphosphatase (F1-ATPase) have been prepared by reaction with 7-chloro-4-nitro-2,1,3-benzoxadiazole (NBD-Cl): a directly labeled product denoted by O-beta'-NBD-F1 and an indirectly prepared product denoted by 0-beta'-NBD-F1. The normal isomer O-beta'-NBD-F1 is highly inhibited, and its label can be removed by 20 microM N-acetyl-L-cysteine (AC) at the expected rate with dr/dn approximately equal to -1, where n is the molar ratio of the label to F1 and r is the ratio of the ATPase activity of the labeled enzyme to that of the unlabeled control enzyme. But O-beta"-NBD-F1 is almost fully active, and its label can be removed by 20 microM AC at much slower rates with dr/dn approximately equal to 0. Cleavage of either isomer with pepsin and subsequent amino acid analysis of the isolated radioactive polypeptides show that the label is attached to Tyr-beta 311 in both isomers. At pH 9 the label in O-beta'-NBD-F1 spontaneously transfers from Tyr-beta 311 to the presumably nearby Lys-beta 162 in the dark with a half-time of 1/2 h, but the label in O-beta"-NBD-F1 does not transfer under the same conditions. The existence of geometric isomers of O-NBD-F1 with contrastingly different properties invalidates models for F1 with three equivalent beta subunits but is consistent with the model based on one principal catalytic beta' subunit and two auxiliary beta" subunits. A possible mechanism for promoting the catalytic efficiency of beta' through protein conformation change induced by ATP and/or ADP is suggested.
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PMID:Geometric isomers of covalently labeled mitochondrial F1-adenosinetriphosphatase with different properties. 287 62

The affinity reagents 3'-O-(5-fluoro-2,4-dinitrophenyl)ADP ether (FDNP-ADP) and 3'-O-(5-fluoro-2,4-dinitrophenyl)ATP ether (FDNP-ATP) were synthesized and characterized. FDNP[14C]ADP was found to label the active site of mitochondrial F1-ATPase slowly at room temperature but with high specificity. F1 was effectively protected from the labeling reagent by ATP or ADP. An average number of 1.3 covalent label per F1 is sufficient for 100% inhibition of the ATPase. About 73% of the radioactive label was found covalently attached to beta subunits, 9% on alpha, practically none on gamma, delta, and epsilon. Cleavage of the labeled enzyme by pepsin and sequencing of the major radioactive peptide showed that the labeled amino acid residue in beta subunit was Lys beta 162. These results show that Lys beta 162 is indeed at the active site of F1 as assumed in the recently proposed models (Fry, D. C., Kuby, S. A., and Mildvan, A. S. (1986) Proc. Natl. Acad. Sci. U. S. A. 83, 907-911; Duncan, I. M., Parsonage, D., and Senior, A. E. (1986) FEBS Lett. 208, 1-6).
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PMID:3'-O-(5-fluoro-2,4-dinitrophenyl)ADP ether and ATP ether. Affinity reagents for labeling ATPases. 290 10

An alkylating ATP analogue, gamma-[4-(N-2-chlorethyl-N-methylamino)]benzylamide ATP (C1RATP), covalently binds to the catalytic alpha-subunit of Na+, K+-ATPase yielding a product resistant to hydrolysis by the enzyme and inhibiting the ATP-hydrolysing activity. The Na+-form of the membrane-bound Na+, K+-ATPase modified with C1RATP was hydrolysed by pepsin under conditions providing maximum stability of the modification product (4 degrees C, pH 1.5). The modified peptide was isolated by HPLC and its amino acid sequence was found to involve residues 706-713 of the alpha-subunit polypeptide chain. This fragment located near the gamma-phosphate of ATP is a component of the active site. It is highly homologous with corresponding regions of the catalytic subunits of all the known E1-E2 ATPases. In the Na+-(or E1-)enzyme form Asp-710 is the target of modification. Evidently E1- and E2-enzymes have different targets in C1RATP modification, i.e. the polypeptide chain regions near the ATP gamma-phosphate in the enzyme active site differ somewhat in their conformations.
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PMID:Affinity modification of E1-form of Na+, K+-ATPase revealed Asp-710 in the catalytic site. 303 72

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of omeprazole are reviewed. Omeprazole, a substituted benzimidazole, has a unique site and mechanism of action because it inhibits the proton pump--i.e., hydrogen, potassium adenosine triphosphatase (H+,K+-ATPase)--and consequently blocks the final common step in the gastric acid secretory pathway. Omeprazole inhibits basal and histamine-, gastrin- and pentagastrin-stimulated gastric hydrochloric acid secretion. It produces a dose-dependent reduction in gastric acidity, gastric acid output, and gastric juice volume and has variable effects on pepsin secretion. Omeprazole has no documented effect on esophageal motility or lower esophageal sphincter pressure. Omeprazole is variably absorbed from the gastrointestinal tract, and food appears to decrease the rate, but not the extent, of drug absorption. The drug is approximately 95% bound to plasma proteins and is metabolized to inactive components that are enterohepatically or renally eliminated. Omeprazole is more effective (in most studies) than H2-receptor antagonists in treating duodenal ulcer, at least as effective in treating benign gastric ulcer, and more effective in treating reflux esophagitis. Omeprazole has been used successfully in patients with Zollinger-Ellison syndrome refractory to treatment with H2-receptor antagonists. Gastrointestinal complaints (nausea and diarrhea) are the most commonly reported adverse effects associated with omeprazole therapy. The most frequently reported laboratory abnormality occurring with omeprazole use is elevation of serum aspartate aminotransferase and alanine aminotransferase concentrations. Omeprazole will serve a valuable role in the management of gastrointestinal tract ulcers and hypersecretory conditions.
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PMID:Therapeutic evaluation of omeprazole. 306 85


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