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)

The use of methenamine in the treatment of urinary tract infections due to Proteus species is limited by urine alkalinity. Acetohydroxamic acid, an inhibitor of urease, maintains acidity despite growth of Proteus in urine. Easily achievable concentrations of acetohydroxamic acid in vitro systems that simulated the dynamics of the urinary tract potentiated the antibacterial effect of methenamine against Proteus species. The combined use of a urease inhibitor and methenamine may be effective in the treatment of urinary infection caused by these organisms.
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PMID:Further observations on the potentiation of the antibacterial effect of methenamine by acetohydroxamic acid. 0 73

The hydrolysis of urea by the bacterial enzyme urease pathologically increase urinary ammonia, bicarbonate, carconate and alkalinity. These factors contribute to the formation of urinary stones and to the virulence of bacteria. Acetohydroxamic acid, a potent inhibitor of urease, has been administered to 23 patients with staghorn renal calculi and urea-splitting urinary infection. Urinary ammonia and alkalinity has been reduced in every patient. A dose of 1.0 gm. acetohydroxamic acid daily has been well tolerated and effective for 2 to 12 months, even in patients with impaired renal function.
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PMID:Acetohydroxamic acid: clinical studies of a urease inhibitor in patients with staghorn renal calculi. 2 42

One hundred forty-eight drugs and other organic and inorganic substances were screened for their ability to inhibit the enzyme urease in an in vitro system modeled on infected urine. The reported urease-inhibiting properties of ascorbic acid, tetracyclines, and sulfanilamide were not confirmed. At least 50 per cent inhibition was observed in the presence of kanamvcin, hydroxguanidine, benzoquinone, 1,2-naphthaquinone-4-sulfonate, chloramine-T, N-bromoacetamide, copper, mercury, and fluoride. It is, however, unlikely that therapeutically effective concentrations can be attained in urine without giving dosages likely to result in toxic effects. Hydroxyurea, at the dose level used in cytotoxic therapy, may be expected to produce effective inhibition of bacterial urease in the urinary tract, providing renal function is unimpaired and providing urinary volume does not exceed 1 liter per 24 hr. Acetohydroxamic acid is potentially the most useful drug for the treatment of infection-induced urinary stone disease available at present.
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PMID:Inhibition of urease by miscellaneous ions and compounds. Implications for the therapy of infection-induced urolithiasis. 90 16

Struvite bladder calculi were induced in rats with an intrarenal injection of urease-producing human T mycoplasma strain T960. Acetohydroxamic acid was effective in inhibiting calculous formation. Methylene blue, tetracycline, orthophosphate, diphosphonate, and hydrochlorothiazide had no inhibitory effect.
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PMID:Medical therapy of experimental infection stones. 91 29

Several lines of evidence suggest that bacterial urease is the primary cause of infection-induced urinary stones. The hydroxamate group of compounds are specific urease inhibitors. Of the cogeners studied, to dat, AHA (acetohydroxamic acid) appears to have the most pharmacologic potential. AHA is rapidly and completely absorbed from the gastrointestinal tract and is concentrated and excreted in the urine. In animals it appears to be relatively nontoxic. Although its toxicity in human beings has not been studied, its similarity to hydroxyurea suggests that reversible toxicity involving the gastrointestinal tract and the hematopoietic systems may result when high doses are administered. The only known metabolite of AHA is acetamide which is nontoxic and rapidly excreted in the urine. Pharmacologic use of AHA is expected to be practical and relatively safe. Use of AHA in patients with urinary infections caused by urea-splitting bacteria may reduce pathogenicity of the infecting organism and may lead to prevention and/or dissolution of stones commonly associated with such infections.
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PMID:Acetohydroxamic acid. Potential use in urinary infection caused by urea-splitting bacteria. 111 89

Urease activity of 50 Helicobacter pylori (H. pylori) strains was assessed employing a photometric assay. Urea hydrolysis reached a maximum in the late log-phase and during the plateau phase of bacterial growth. The reaction time of H. pylori urease was significantly shorter than that of other urease producing bacteria (P. mirabilis, P. vulgaris, K. pneumoniae, K. oxytoca). Increasing the reaction temperature hardly led to an acceleration of the quick urea hydrolysis of H. pylori, in contrast to the situation with P. mirabilis. Acetohydroxamic acid showed a dose-dependent non-competitive suppression of urease production, whereas 9 antibiotics in subinhibitory concentrations did not influence urease production of H. pylori.
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PMID:Urease production by Helicobacter (Campylobacter) pylori. 193 May 66

Concentrated broth culture supernatants from 50 to 60% of Helicobacter pylori strains induce eukaryotic cell vacuolation in vitro. A quantitative assay for cell vacuolation was developed on the basis of the rapid uptake of visibly vacuolated HeLa cells was significantly greater than that of nonvacuolated cells. By using the rapid NRU assay, we sought to determine the roles of H. pylori cytotoxin, urease, and ammonia in the vacuolation of HeLa cells. The NRU of HeLa cells incubated in medium containing ammonium chloride or ammonium sulfate was significantly greater than that of cells incubated in medium alone. In addition, ammonium salts augmented the NRU induced by H. pylori supernatants. The NRU induced by jack bean urease was augmented by the addition of urea to cell culture medium; this suggests that urease-mediated NRU occurs via the generation of ammonia. Acetohydroxamic acid blocked the NRU induced by jack bean urease and urea but failed to block the uptake induced by H. pylori supernatants. Supernatant from a non-urease-producing H. pylori mutant strain induced NRU identical to that of the urease-positive parental strain. These observations indicate that the vacuolating activity in H. pylori supernatants is not mediated solely by urease activity but that it may be potentiated by urease-mediated ammonia production.
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PMID:Effect of urease on HeLa cell vacuolation induced by Helicobacter pylori cytotoxin. 200 8

We examined several compounds for their mechanisms of inhibition with the nickel-containing active site of homogeneous Klebsiella aerogenes urease. Thiolate anions competitively inhibit urease and directly interact with the metallocenter, as shown by the pH dependence of inhibition and by UV-visible absorbance spectroscopic studies. Cysteamine, which possesses a cationic beta-amino group, exhibited a high affinity for urease (Ki = 5 microM), whereas thiolates containing anionic carboxyl groups were uniformly poor inhibitors. Phosphate monoanion competitively inhibits a protonated form of urease with a pKa of less than 5. Both the thiolate and phosphate inhibition results are consistent with charge repulsion by an anionic group in the urease active site. Acetohydroxamic acid (AHA) was shown to be a slow-binding competitive inhibitor of urease. This compound forms an initial E.AHA complex which then undergoes a slow transformation to yield an E.AHA* complex; the overall dissociation constant of AHA is 2.6 microM. Phenylphosphorodiamidate, also shown to be a slow-binding competitive inhibitor, possesses an overall dissociation constant of 94 pM. The tight binding of phenylphosphorodiamidate was exploited to demonstrate the presence of two active sites per enzyme molecule. Urease contains 4 mol of nickel/mol enzyme, hence there are two nickel ions/catalytic unit. Each of the two slow-binding inhibitors are proposed to form complexes in which the inhibitor bridges the two active site nickel ions. The inhibition results obtained for K. aerogenes urease are compared with inhibition studies of other ureases and are interpreted in terms of a model for catalysis proposed for the jack bean enzyme (Dixon, N.E., Riddles, P.W., Gazzola, C., Blakely, R.L., and Zerner, B. (1980) Can. J. Biochem. 58, 1335-1344).
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PMID:Competitive inhibitors of Klebsiella aerogenes urease. Mechanisms of interaction with the nickel active site. 267 18

Acetohydroxamic acid is known to inhibit bacterial urease activity, thus, reducing urinary ammonia levels. A double-blind placebo-controlled clinical trial of acetohydroxamic acid was conducted at 12 Veterans Administration spinal cord injury units. A total of 210 male spinal cord injury patients with chronic urea-splitting urinary infection was enrolled for a scheduled followup of 2 years. The study data support the usefulness of acetohydroxamic acid in reducing urinary ammonia. At every followup visit the acetohydroxamic acid patients with stones had decreases in ammonia of 30 to 48 mg. per dh., while the placebo patients had increases in ammonia. Acetohydroxamic acid also retarded stone growth. Patients with stones treated with acetohydroxamic acid exhibited significantly longer intervals from randomization to first stone growth than patients treated with placebo (p less than 0.005, medians 15 versus 9 months). Acetohydroxamic acid reduced significantly the proportion of patients with stone growth at 12 months (33 versus 60 per cent, p equals 0.017). This decrease was diminished at 24 months (42 versus 60 per cent, p equals 0.260). Patient attrition was 31 per cent in the placebo group and 62 per cent in the acetohydroxamic acid group, the latter attrition being primarily owing to patient request because of mild symptoms. Of the acetohydroxamic acid and placebo patients 62 and 29 per cent, respectively, reported drug side effects but all were reversible and no unanticipated or life-threatening reactions occurred.
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PMID:A randomized trial of acetohydroxamic acid for the treatment and prevention of infection-induced urinary stones in spinal cord injury patients. 329 42

Campylobacter pylori, a suspected agent of gastritis and peptic ulceration, rapidly hydrolyzes urea. Because urease serves as the basis of detection of the organism in gastric biopsies and may represent an important virulence factor, biochemical characteristics of the enzyme were determined. C. pylori was isolated from antral biopsies from 10 patients with complaints of abdominal pain or history of peptic ulcer disease. All isolates were urease positive, with an average rate of hydrolysis by cell lysates being 36 +/- 28 mumol of NH3 per min per mg of protein, more than twice that of Proteus mirabilis and 10 times that of other urinary tract isolates. The enzyme had an apparent molecular weight of 625,000 +/- 15,000 by column chromatography, an isoelectric point of 5.9, a Km of 0.8 +/- 0.1 mM urea, an optimal temperature of 45 degrees C, and an optimal pH of 8.2. Ten isolates tested produced ureases with identical electrophoretic mobilities on nondenaturing 5% polyacrylamide activity gels. Acetohydroxamic acid (100 micrograms/ml), hydroxyurea (85 micrograms/ml), flurofamide (0.05 micrograms/ml), and EDTA (8 mM) inhibited enzyme activity by 50%. Cell lysates retained 50% of initial urease activity after 6 days and 40% activity after 18 days when stored at 4 degrees C in 20 mM sodium phosphate, pH 6.8. At -70 degrees C for 18 days, 1 mM EDTA or 15% glycerol preserved 40 or 34%, respectively, of initial activity. The urease of C. pylori appears to be biochemically unique from the enzymes of other common urease-producing species.
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PMID:Characterization of urease from Campylobacter pylori. 338 8


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