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:6.3.4.6 (urease)
7,490 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Helicobacter pylori (Hp) is considered as the major pathogen in Hp-associated gastritis but the mechanism of its action has not been fully explained. We investigated both the damaging and protective effects of intragastric (i.g.) application of ammonia (NH4OH) and ammonium ion (NH4Cl), the major products of Hp-derived urease, on the rat stomach with intact and capsaicin-deactivated sensory nerves or suppressed prostaglandin (PG) and nitric oxide (NO) synthesis. NH4OH given i.g. resulted in a concentration-dependent mucosal damage starting at 30 mM and reaching maximum at 250 mM (pH 11), the extent of damage being similar to that obtained with 100% ethanol. NaOH solution (1 mM) at pH 11 given i.g. did not affect mucosal integrity. The damage caused by NH4OH was accompanied by the fall in gastric blood flow (GBF) reaching at 250 mM NH4OH about 30% of the vehicle control value. The NH4OH-induced gastric damage was augmented by capsaicin-induced deactivation of sensory nerves, the suppression of nitric oxide (NO) synthase with L-NAME or the decrease of i.g. acidity by ranitidine. The pretreatment with scavengers of reactive oxidants significantly reduced the area of NH4OH-induced gastric lesions. When the mucosa was first exposed to a low 15-mM concentration of NH4OH and then insulted with large 250 mM NH4OH or with 100% ethanol, the lesion area was markedly reduced as compared to that obtained with 250 mM NH4OH or 100% ethanol alone. This adaptive protection by 'mild' concentration of NH4OH against strong irritants (250 mM NH4OH or 100% ethanol) was reversed, in part, by pretreatment with L-NAME and indomethacin. NH4Cl (60-500 mM) given i.g. alone failed to affect the mucosal integrity but when applied before 100% ethanol it produced a concentration-dependent fall in the mucosal damage by these irritants. We conclude that; (1) ammonia at higher concentrations damages the gastric mucosa, while ammonium ion exerts the protective activity; (2) the ammonia-induced gastric damage may involve the formation of reactive oxidants; (3) ammonia at lower concentration acts like a mild irritant via the activation of sensory nerves, NO-arginine pathway and PG.
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PMID:Gastric mucosal damage and adaptive protection by ammonia and ammonium ion in rats. 891 6

Helicobacter pylori has been established as the major causative agent of human active gastritis and is an essential factor in peptic ulcer disease and gastric cancer. The mechanism that has been proposed for H. pylori to control its inhospitable microenvironment happens to coincide with the pH control technique developed by us. This technique was developed to separate an acidic environment from a basic environment for a sequential enzymatic reaction by the hydrolysis of urea within a thin layer of immobilized urease. In this paper, a mathematical model is presented to consider how H. pylori survives the gastric acidity. The computed results explain well the experimental data available involving H. pylori.
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PMID:Helicobacter pylori survival in gastric mucosa by generation of a pH gradient. 925 24

It has been suggested that oral dissemination might be the major transmission vehicle for Helicobacter pylori, and that dental plaque might act as its reservoir. The presence of H. pylori was investigated in 62 odontological male and female patients (average age: 35 years old). Samples were taken from supragingival plaque, placed in 0.3 ml of thioglycolate broth, cultured within 12 h in Mueller-Hinton agar with the addition of 5-7% of sheep blood and antibiotic supplement, and incubated at 37 degrees C in microaerophilia for 5-7 days. Typical colonies were identified by gram, urease, oxidase and catalase. H. pylori was detected in a 15 year-old patient suffering from gastric acidity (1.61% positivity index). The medium used facilitated recovery of the agent from a sample abundant in germs. H. pylori was not recovered from the same patient 12 months later, suggesting that there might have been a transitory passage by gastric reflux or that the bacterium was acquired from an exogenous source.
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PMID:[Isolation of Helicobacter pylori from dental plaque]. 974 36

The ability of Helicobacter pylori to survive in the varying acidity of the stomach is considered to be linked to its ability to maintain a tolerable pH in its periplasmic space by acid dependent activation of internal urease activity. Whereas survival of H pylori can occur between a periplasmic pH of 4.0 to 8.0, growth can only occur between a periplasmic pH of 6.0 to 8.0. When urease activity is only able to elevate periplasmic pH to between 4.0 and 6.0, the organisms will survive but not divide. In the absence of division, antibiotics such as clarithromycin and amoxycillin are ineffective. Proton pump inhibitors, by elevating gastric pH, would increase the population of dividing organisms and hence synergise with these antibiotics.
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PMID:The life and death of Helicobacter pylori. 976 42

Two problems can be identified as possible long term negative consequences of HP eradication: diminished efficacy of acid-lowering drugs, and an accelerated development of GERD. It was shown that omeprazole produces a greater decrease in gastric acidity in subjects with H. pylori infection than in those who are H. pylori negative, and that omeprazole produces a smaller decrease in gastric acidity after cure of H. pylori. This effect persisted for at least one year after HP eradication. It is not limited to omeprazole, but can also be seen with the H2 receptor antagonist ranitidine. At least one proven mechanism involved in this phenomenon is the disappearance of the alkalinizing effect of ammonia, generated from urea by HP's urease, after eradication of the bacteria; other mechanisms may also be involved. HP eradication may therefore potentially hamper acid inhibitory treatment. It is unknown to what extent this is clinically relevant. Although one study did not observe a relation between H. pylori status and efficacy of omeprazole maintenance therapy for GERD, it cannot be excluded that some patients may need more potent or higher doses of acid-lowering medication after HP eradication. Three studies suggest that duodenal ulcer patients who were successfully treated with H. pylori eradication therapy, may be at increased risk to develop GERD. Labenz's study finds that the incidence of GERD may be double 3 years after eradication. The life-table analysis suggested that cure of the infection was associated with an increased risk of reflux oesophagitis during the first year after treatment, whereas later the incidence of reflux oesophagitis was similar in both groups. Patients who developed reflux oesophagitis after the cure had a more severe body gastritis before cure, gained weight more frequently after cure, and were predominantly men. There are no data on the fate of the oesophagus after HP eradication in patients with reflux oesophagitis. The data thus strongly suggest that there is a risk for developing reflux oesophagitis after HP eradication in patients with duodenal ulcer. It is unknown whether HP eradication in patients without duodenal ulcer also increases the risk for developing reflux oesophagitis.
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PMID:Adverse events of HP eradication: long-term negative consequences of HP eradication. 979 71

Helicobacter pylori has adapted to a very specialized niche; namely, the highly acidic, viscous, and somewhat anaerobic gastric mucus of humans. The enzyme urease is essential for colonization of the stomach, as it provides protection against gastric acidity. A spiral morphology as well as sheathed flagella have been claimed to give the bacteria an advantage in colonizing mucus. Wild type strain of H. pylori and its isogenic urease-negative mutant showed a chemotactic response to urea, flurofamide (a potent urease inhibitor), sodium ion, and bicarbonate ion. These chemotactic responses are also observed in the viscous environment. Thus, it appears that H. pylori has chemotactic movement that is independent of urease activity. The chemotactic response was inhibited by carbonyl cyanide m-chlorophenylhydrazone (CCCP), a potent H+ pump inhibitor, but not by Na+ pump-inhibiting amiloride, suggesting this response is forced by H+-driven flagellar movement. Since urea and sodium bicarbonate are secreted from the gastric epithelial surface, this chemotactic response may contribute to the colonization by H. pylori and the persistence of its infection.
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PMID:Chemotaxis of Helicobacter pylori: a urease-independent response. 984 7

Helicobacter pylori urease is required to counteract acidity during colonization of the stomach, and has been suggested as a major immunodominant antigen. The aim of this study was to determine the anti-urease response in a representative national serologic survey in Mexico. The population surveyed included persons 1-90 years of age from all socioeconomic levels and geographic zones of the country. Helicobacter pylori status was determined by ELISA serology. The IgG anti-urease was studied by ELISA using a recombinant apoenzyme. We found that 2,930 of the 7,720 infected patients (38%) were seropositive for IgG urease. The rate of IgG anti-urease positivity increased with age; in children < 10 years old it was < 20% and in persons > 40 years old it was > 50%. Age and a region with a high level of development were risk factors for seropositivity, whereas gender, educational level, crowding, and socioeconomic level were not associated with seropositivity. In conclusion, in natural infection with H. pylori, the response to urease is poor, mainly during the first years of infection. This inconsistent immune response to the enzyme may favor persistence of infection. A vaccine eliciting a consistent anti-urease response might overcome immune evasion and enhance clearance of bacteria after exposure.
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PMID:Serologic IgG response to urease in Helicobacter pylori-infected persons from Mexico. 1034 33

Rabeprazole sodium is a new substituted benzimidazole proton pump inhibitor with several differences compared with existing proton pump inhibitors. In vitro and animal studies have demonstrated that rabeprazole is a more potent inhibitor of H+,K(+)-ATPase and acid secretion than omeprazole, and is a more rapid inhibitor of proton pumps than omeprazole, lansoprazole, or pantoprazole. This probably reflects rabeprazole's faster activation in the parietal cell canaliculus. In human studies, once-daily doses of 5-40 mg of rabeprazole inhibit gastric acid secretion in a dose-dependent fashion. A once-daily dose of 20 mg has consistently achieved profound decreases in 24-h intragastric acidity in single and repeat dosing studies, in healthy volunteers and patients with either peptic ulcer disease or gastro-oesophageal reflux disease. Significantly greater decreases in intragastric acidity are achieved on day 1 of dosing with rabeprazole 20 mg than with omeprazole 20 mg. As with other proton pump inhibitors, rabeprazole has in vitro antibacterial activity against Helicobacter pylori, with greater activity against this organism than either lansoprazole or omeprazole. In addition to inhibiting bacterial urease activity, rabeprazole binds to several molecules on H. pylori. Clinical trials are needed to assess the clinical importance of these findings, as well as to assess whether the potential advantages of rabeprazole result in clinical benefit for patients with acid-related diseases.
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PMID:Review article: the pharmacology of rabeprazole. 1049 23

Klebsiella aerogenes urease uses a dinuclear nickel active site to catalyze urea hydrolysis at >10(14)-fold the spontaneous rate. To better define the enzyme mechanism, we examined the kinetics and structures for a suite of site-directed variants involving four residues at the active site: His320, His219, Asp221, and Arg336. Compared to wild-type urease, the H320A, H320N, and H320Q variants exhibit similar approximately 10(-)(5)-fold deficiencies in rates, modest K(m) changes, and disorders in the peptide flap covering their active sites. The pH profiles for these mutant enzymes are anomalous with optima near 6 and shoulders that extend to pH 9. H219A urease exhibits 10(3)-fold increased K(m) over that of native enzyme, whereas the increase is less marked ( approximately 10(2)-fold) in the H219N and H219Q variants that retain hydrogen bonding capability. Structures for these variants show clearly resolved active site water molecules covered by well-ordered peptide flaps. Whereas the D221N variant is only moderately affected compared to wild-type enzyme, D221A urease possesses low activity ( approximately 10(-)(3) that of native enzyme), a small increase in K(m), and a pH 5 optimum. The crystal structure for D221A urease is reminiscent of the His320 variants. The R336Q enzyme has a approximately 10(-)(4)-fold decreased catalytic rate with near-normal pH dependence and an unaffected K(m). Phenylglyoxal inactivates the R336Q variant at over half the rate observed for native enzyme, demonstrating that modification of non-active-site arginines can eliminate activity, perhaps by affecting the peptide flap. Our data favor a mechanism in which His219 helps to polarize the substrate carbonyl group, a metal-bound terminal hydroxide or bridging oxo-dianion attacks urea to form a tetrahedral intermediate, and protonation occurs via the general acid His320 with Asp221 and Arg336 orienting and influencing the acidity of this residue. Furthermore, we conclude that the simple bell-shaped pH dependence of k(cat) and k(cat)/K(m) for the native enzyme masks a more complex underlying pH dependence involving at least four pK(a)s.
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PMID:Kinetic and structural characterization of urease active site variants. 1091 64

Helicobacter pylori resists gastric acidity by modulating the proton-gated urea channel UreI, allowing for pH(out)-dependent regulation of urea access to intrabacterial urease. We employed pH- and Ca(2+)-sensitive fluorescent dyes and confocal microscopy to determine the location, rate, and magnitude of pH changes in an H. pylori-AGS cell coculture model, comparing wild-type bacteria with nonpolar ureI-deletion strains (ureI-ve). Addition of urea at pH 5.5 to the coculture resulted first in elevation of bacterial periplasmic pH, followed by an increase of medium pH and then pH in AGS cells. No change in periplasmic pH occurred in ureI-deletion mutants, which also induced a slower increase in the pH of the medium. Pretreatment of the mutant bacteria with the detergent C(12)E(8) before adding urea resulted in rapid elevation of bacterial cytoplasmic pH and medium pH. UreI-dependent NH(3) generation by intrabacterial urease buffers the bacterial periplasm, enabling acid resistance at the low urea concentrations found in gastric juice. Perfusion of AGS cells with urea-containing medium from coculture at pH 5.5 did not elevate pH(in) or [Ca(2+)](in), unless the conditioned medium was first neutralized to elevate the NH(3)/NH(4)(+) ratio. Therefore, cellular effects of intrabacterial ammonia generation under acidic conditions are indirect and not through a type IV secretory complex. The pH(in) and [Ca(2+)](in) elevation that causes the NH(3)/NH(4)(+) ratio to increase after neutralization of infected gastric juice may contribute to the gastritis seen with H. pylori infection.
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PMID:Local pH elevation mediated by the intrabacterial urease of Helicobacter pylori cocultured with gastric cells. 1093 Apr 37


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