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 gastric acid antisecretory compound omeprazole (5-methoxy-2-((4-methoxy- 3,5-dimethyl-2-pyridinylmethyl)-sulphinyl)-1H-benzimidazole), a member of the new class of H+, K(+)-ATPase inhibitors, is known to interact with the metabolism of other drugs in vitro and in vivo. In this study, two other substituted benzimidazoles, pantoprazole (5-difluoromethoxy-2-((3,4-di-methoxy-2-pyridinylmethyl)-s ulp hinyl)-1H- benzimidazole) and lansoprazole (2-((3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinylmethyl)- sulphinyl)-1H-benzimidazole) are compared for their ability to inhibit cytochrome P450 dependent biotransformation in vitro with regard to three representative reactions: O-dealkylation of 7-ethoxycoumarin (EC), N-demethylation of ethylmorphine (EM) and hydroxylation of lonazolac (Lona). These reactions can be seen in microsomes from phenobarbital pretreated rats representing the cytochrome P450IIB1 subfamily. As shown in presence of known inhibitors of cytochrome P450, e.g. SK&F 525A, metyrapone, chlorpromazine and nitrendipine, different enzymes seem to be responsible for these three indicator reactions of the cytochrome P450IIB1 complex. These reactions are inhibited to a different extent by the three H+, K(+)-ATPase inhibitors. Pantoprazole shows the lowest inhibitory activity versus the three reactions (Ki, mumol/L): EC, 138; EM, 104; Lona, 128. A greater effect is observed with omeprazole: EC, 38; EM, 68; Lona, 20. Lansoprazole exceeds omeprazole in inhibiting the three cytochrome P450 dependent enzymes: EC, 17; EM, 34; Lona, 8. In microsomes from untreated rats with the predominant cytochrome P450IIA1 subfamily as well as in microsomes from isopropanol treated rats (induction of cytochrome P450IIE1) which catalyse only lonazolac hydroxylation to a detectable amount, the latter reaction was inhibited by pantoprazole with a somewhat lower Ki of 77 whereas the values for omeprazole and lansoprazole remained unchanged in comparison to those found in microsomes from phenobarbital pretreated rats. The biotransformation rate of the substituted benzimidazoles themselves in microsomes from control and induced rats is lowest for pantoprazole followed by lansoprazole and omeprazole.
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PMID:The H+, K(+)-ATPase inhibitor pantoprazole (BY1023/SK&F96022) interacts less with cytochrome P450 than omeprazole and lansoprazole. 165 Feb 12

Disruption of the gene for subunit 6 of the yeast cytochrome bc1 complex (QCR6) causes a temperature-sensitive petite phenotype in contrast to deletion of the coding region of QCR6, which shows no growth defect. Mitochondria from the petite strain carrying the disruption allele were devoid of ubiquinol-cytochrome c oxidoreductase activity but retained cytochrome c oxidase and oligomycin-sensitive ATPase activities. Optical spectra of cytochromes in mitochondrial membranes from the petite strain lacked a cytochrome b absorption band and had a reduced amount of cytochrome c1. Analysis of mitochondrial translation products showed normal synthesis of cytochrome b. Western analysis of mitochondrial membranes from this disruption strain indicates core protein 1 of the cytochrome bc1 complex is present in normal amounts, while cytochrome c1, the Rieske iron-sulfur protein, subunit 6, and subunit 7 were absent or present in very low amounts. Taken together, these findings indicate a loss of assembly of the cytochrome bc1 complex. High copy suppressors of the disruption strain were selected. Two separate families of suppressors were found. The first contained QCR6. The second family consisted of overlapping clones of a second gene distinct from QCR6. These plasmids contained QCR9, the gene which codes for subunit 9 of the yeast cytochrome bc1 complex. Suppression of the QCR6 disruption strain by overexpression of QCR9 indicates a critical interaction between these two proteins in the assembly of the cytochrome bc1 complex.
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PMID:The petite phenotype resulting from a truncated copy of subunit 6 results from loss of assembly of the cytochrome bc1 complex and can be suppressed by overexpression of subunit 9. 165 16

Almost 10% of adverse drug reactions observed in clinical patients are due to interactions of two or more therapeutic agents (18). The aim of the present study was to investigate in vivo interactions of the H2-blocker cimetidine and three newly developed H+/K(+)-ATPase inhibitors, omeprazole, lansoprazole and pantoprazole (BY 1023/SK&F 96022) with cytochrome P 450 in rats. Because diazepam is a drug used very often as comedication in ulcer patients, the duration of the effects of diazepam on muscle coordination were used to evaluate the drug interactions on metabolic enzymes. The present data indicate a clear rank order of the antiulcer drugs' potency for interaction with diazepam: 1) lansoprazole with a 50% prolongation of diazepam effect at 170 mumol/kg, 2) cimetidine and omeprazole at 281 and 288 mumol/kg, respectively and 3) pantoprazole at greater than 1000 mumol/kg. Because the three H+/K(+)-ATPase inhibitors are approximately equipotent with respect to inhibition of gastric acid secretion, it can be concluded that pantoprazole is superior to omeprazole and lansoprazole when unwanted adverse effects with drug metabolizing enzymes are considered. This may be an advantage in clinical use of the drug.
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PMID:In vivo cytochrome P 450 interactions of the newly developed H+/K(+)-ATPase inhibitor pantoprazole (BY 1023/SK&F 96022) compared to other antiulcer drugs. 165 32

Enzyme-histochemical studies were conducted on livers of mice chronically fed griseofulvin (GF) in order to produce Mallory bodies (MBs) in hepatocytes. The development of MBs is associated with derangement of the immunohistochemically detectable intermediate filament (IF) cytoskeleton of the cytokeratin (CK) type, although no strict correlation between appearance or involution of MBs and the cytoskeletal alterations exists. Since the function of the IF cytoskeleton and the relationship of its disturbance to cell injury is unknown, the aim of the present study was to correlate the activities of several key enzymes of cellular metabolic pathways with the disturbance of the cytoskeleton architecture. For that purpose enzyme-histochemistry in combination with immunohistochemical CK-IF stainings were performed on identical sections. In GF-intoxicated mouse livers the normal topography of enzyme activities was disturbed, but no strict colocalization of enzymatic and cytoskeletal changes was found. Glucose-6-phosphatase, a microsomal enzyme involved in glucose output and gluconeogenesis, showed elevated activity in MB-free hepatocytes with diminished immunostainable CK-IF cytoskeleton refuting the concept of a disability of those cells to export glucose. It could indeed indicate that those cells without MBs are in the state of recovery. However, these cells could also resemble "hyperactive foci". Glycogen was decreased in MB-containing hepatocytes with disturbed cytoskeleton, and this feature favours the assumption of cell degeneration. On the other hand, the mitochondrial marker enzymes, i.e. succinate dehydrogenase, cytochrome-c-oxidase and 3-hydroxybutyrate dehydrogenase, remained unchanged in altered hepatocytes. Alkaline phosphatase activity at the canalicular pole of GF-intoxicated hepatocytes was elevated, indicating cholestatic features associated with this disorder. However, since altered hepatocytes did not show impairment of oxido-reductase activities, a severe impairment of bile secretion as a consequence of cell damage is unlikely. Unchanged or even increased ATPase activity of altered hepatocytes also indicated their sustained metabolic abilities. The results presented provide indirect evidence that hepatocytes with disturbed IF cytoskeleton do not significantly differ from normal cells with respect to oxidative metabolism, fatty acid synthesis and gluconeogenesis. This suggests that alterations of the IF cytoskeleton associated with GF intoxication and MB formation have no significant adverse influence on the metabolic functions of liver cells, as far as can be assessed by evaluation by enzyme-histochemical staining of several key enzymes.
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PMID:Enzyme-histochemical studies of griseofulvin-intoxicated mouse livers. 165 25

To investigate the functional stages of osteoclasts, the ultrastructural histochemical distribution of the lysosomal enzymes [acid phosphatase (tartrate-sensitive) and neutral phosphatase], the plasma membrane enzymes [alkaline phosphatase, Ca(++)-ATPase, and alkaline ouabain-insensitive p-nitrophenylphosphatase (alkaline p-NPPase)], and the mitochondrial enzyme (cytochrome C oxidase) was evaluated in the chicken tibial metaphysis. Both active-appearing and detached (resting) osteoclasts were studied. Serial sectioning was used to identify detached osteoclasts which were present in the perivascular space. The ultrastructure of detached osteoclasts was similar to that of active osteoclasts, except for the lack of a ruffled border and clear zone, and an altered distribution pattern of small vesicles. Small vesicles were uniformly distributed in the cytoplasm of resting osteoclasts, whereas they were concentrated beneath the ruffled border of active osteoclasts. Alkaline p-NPPase, a marker enzyme for the basal ruffled border, was also apparent on the membrane of small vesicles. However, the vesicles did not possess Ca(++)-ATPase, a marker enzyme for the apical plasma membrane. These findings support the concept that small vesicles serve as a membrane reservoir for the ruffled border membrane. Pre-osteoclasts contained abundant mitochondria and lysosomes, prominent Golgi complexes, moderately developed endoplasmic reticulum, and lacked small vesicles. Pre-osteoclasts appear to fuse with osteoclasts which are attached to the bone surface, but not with detached osteoclasts. The small vesicles, from which the ruffled border arises, are absent from pre-osteoclasts, suggesting that they develop after fusion with pre-existing osteoclasts or after attachment to the bone surface. Alkaline p-NPPase appears to be a marker for differentiation of pre-osteoclasts to mature osteoclasts.
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PMID:Characterization of the functional stages of osteoclasts by enzyme histochemistry and electron microscopy. 166 72

The effect of long-term ethanol intake on the structural and functional characteristics of rat skeletal-muscle mitochondria and sarcoplasmic reticulum was investigated. Functionally, skeletal-muscle mitochondria were characterized by a high respiratory control index and ADP/O ratio and a high State-3 respiration rate with different substrates. These parameters were not significantly different in preparations from control and ethanol-fed rats, except for a small increase in the rate of oxidation of alpha-oxoglutarate/malate in the latter. In submitochondrial particles from the two groups of animals there was no significant difference in cytochrome content, ATPase activity or the activity of respiratory-chain complexes. Mitochondrial membranes from untreated and ethanol-fed rats showed no difference in the baseline e.s.r. order parameter, and both preparations were equally sensitive to disordering by ethanol in vitro. Similarly, sarcoplasmic-reticulum preparations were not significantly affected by long-term ethanol feeding with respect to Ca2(+)-ATPase activity or in baseline order parameter and susceptibility to membrane disordering by ethanol in vitro. These membranes were also equally sensitive to degradation by exogenous phospholipase A2. Ethanol feeding did not alter the class composition of mitochondrial or sarcoplasmic-reticulum membrane phospholipids, nor the acyl composition of individual phospholipid classes. Specifically, the changes in acyl composition that characteristically occur in liver microsomal phosphatidylinositol and liver mitochondrial cardiolipin were not observed in the corresponding phospholipids from skeletal-muscle membranes. In experiments where membrane preparations from liver and skeletal muscle from the same ethanol-fed animals were compared, the liver membranes developed membrane tolerance, with the muscle membranes retaining normal sensitivity to disordering effects by ethanol. It is concluded that: (a) different tissues from the same animals differ in their susceptibility to ethanol; (b) the tissue-specific lack of development of membrane tolerance correlates with a lack of chemical changes in the phospholipids and with a retention of normal function of mitochondria and sarcoplasmic reticulum; (c) effects of chronic ethanol intake on muscle function are not due to a defect in the mitochondrial energy supply.
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PMID:Maintenance of structural and functional characteristics of skeletal-muscle mitochondria and sarcoplasmic-reticular membranes after chronic ethanol treatment. 184 61

Previous reports have suggested that the physical properties of cell membranes and calcium homeostasis in both the central and peripheral nervous system are changed in Alzheimer's disease (AD). This study has examined the biophysical properties of erythrocyte and platelet membranes by measuring the fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) and possible related changes in lipid peroxidation. In addition, we have studied calcium homeostasis by measuring thrombin-stimulated changes in intraplatelet free calcium and Ca2(+)-ATPase activity in AD and healthy age and sex-matched controls. Our results show that there was no significant difference in the fluorescence anisotropy of DPH in erythrocyte membranes isolated from the three groups. There was also no significant difference in lipid peroxidation levels in erythrocytes and plasma of AD patients compared to controls. However, there was a significant reduction in the fluorescence anisotropy of DPH in platelet membranes from AD patients, compared with healthy controls. Recent evident suggests that the increase in platelet membrane fluidity results from alterations in internal membranes. We measured the specific activities of enzyme markers associated with intracellular and plasma membranes in platelets from AD patients and healthy controls. There was a significant reduction in the specific activity of antimycin A-insensitive NADH-cytochrome-c reductase (a specific marker for smooth endoplasmic reticulum (SER)), in AD patients compared to controls, but no change in the specific activity of bis(p-nitrophenyl)phosphate phosphodiesterase (a specific marker for plasma membrane). We have also shown that SER mediated [Ca2+] homeostasis is possibly impaired in AD platelets, i.e., the percentage of thrombin-stimulated increase in intraplatelet [Ca2+] above basal levels was significantly higher in AD compared to matched controls and there were significant reductions in the specific activities of Ca2+/Mg2(+)-ATPase and Ca2(+)-ATPase (but not Mg2(+)-ATPase) in AD platelets. Finally electron microscopic analysis of platelets showed that there was a significant increase in the incidence of abnormal membranes in AD patients compared to controls. The ultrastructural abnormalities seem to consist of proliferation of a system of trabeculated cisternae bounded by SER. These results suggest that both SER structure and function might be defected in AD platelets, which could explain the fluidity changes observed here.
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PMID:Platelet and erythrocyte membrane changes in Alzheimer's disease. 214

A procedure for isolating staphylococcal membranes including preprocessing of the cells with 0.1 M solution of cysteine hydrochloride and subsequent differential centrifugation was developed. The procedure is based on enzymatic lysis with an enzyme preparation from Streptomyces recifensis subsp. lyticus 2435. The membrane preparations had oxidase and dehydrogenase activity and were characterized by a high specific activity of the membrane-bound ATPase. Determination of the cytochrome differential spectra revealed the presence of cytochromes a, b and o in the membrane preparations.
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PMID:[Use of enzyme preparation from Streptomyces recifensis subsp. lyticus for isolation of membrane substances from staphylococcal cells]. 214 25

An Escherichia coli mutant pleiotropically altered in membrane-bound oxidoreductase activities was isolated following nitrosoguanidine treatment. Mutant R23 was able to grow on glucose, but was unable to grow on succinate or other oxidizable substrates as a sole energy source. Isolated membranes prepared from R23 failed to oxidize succinate and formate; while NADH was oxidized at a reduced rate by membranes. The mutant also exhibited markedly reduced cytochrome content, but normal DL-lactate PMS reductase and H(+)-translocating ATPase activities relative to the parent strain. Bacteriophage Plkc was used to transduce R23 to growth on glycerol, DL-lactate or succinate; regardless of the selection procedure, each of the 179 transductants had gained the ability to grow on all three substrates. The suc- mutation in R23 appeared to be responsible for the loss of growth on oxidizable substrates, altered membrane-bound oxidoreductase activities, resistance to neomycin, and reduced levels of cytochrome components. The suc- mutation was localized in the 6 to 6.5 min region of the E. coli chromosome map utilizing episomal transfers.
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PMID:Characterization of an Escherichia coli mutant pleiotropically altered in membrane-bound oxidoreductase activities. 214 97

Nitrosoguanidine mutagenesis was employed to isolate an Escherichia coli mutant conditionally altered in respiratory chain components. Mutant R25 was able to grow on glucose, fructose, and glycerol but failed to grow on succinate and acetate (suc-). Also, R25 exhibited leaky growth on DL-lactate, fumarate, and malate (lct*). The lct* mutation pleiotropically affected a number of respiratory chain components and its expression was conditional with the growth substrate. Glucose-grown R25 resting cell suspensions oxidized DL-lactate and formate; however, these two substrates were not oxidized by fructose- or glycerol-grown cell suspensions. The same conditional pattern was observed for the concentration of cytochrome components, the membrane-associated oxidation of NADH and formate, and formate phenazine methosulfate (PMS) reductase activity; succinate oxidase and PMS reductase activities were not exhibited by membranes under any growth condition due to the suc- mutation. R25 membrane-associated H(+)-translocating ATPase activity was not conditional with the growth substrate. R25PC, a spontaneous lct+ suc- partial revertant of R25, did not exhibit the conditional pattern of R25. The lct* mutation was found to map in the 27-30-min region and the suc- mutation in the 15-17-min region of the E. coli genome. Two distinct classes of R25 P1kc transductants were isolated that differed in both their growth response on succinate and DL-lactate and their oxidase activities.
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PMID:An Escherichia coli mutant conditionally altered in respiratory chain components. 215 Feb 14


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