The urea cycle of Helicobacter pylori

Mendz, George L.; Hazell, Stuart L.

doi:10.1099/13500872-142-10-2959

Cited by 79 publications

(48 citation statements)

References 19 publications

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“…These findings indicate that under the experimental conditions in the present study macrophage apoptosis is not altered by potential effects of arginase inhibitors on H. pylori arginase. It should also be recognized that H. pylori can release L-ornithine (60) and produce polyamines, such as agmatine (62), histamine, and spermidine (63). Thus, H. pylori may modulate the immune response by facilitating host polyamine synthesis or by producing the polyamines directly.…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori Induces Macrophage Apoptosis by Activation of Arginase II

Gobert

Cheng

Wang

et al. 2002

The Journal of Immunology

157

201

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Helicobacter pylori infection induces innate immune responses in macrophages, contributing to mucosal inflammation and damage. Macrophage apoptosis is important in the pathogenesis of mucosal infections but has not been studied with H. pylori. NO derived from inducible NO synthase (iNOS) can activate macrophage apoptosis. Arginase competes with iNOS by converting l-arginine to l-ornithine. Since we reported that H. pylori induces iNOS in macrophages, we now determined whether this bacterium induces arginase and the effect of this activation on apoptosis. NF-κB-dependent induction of arginase II, but not arginase I, was observed in RAW 264.7 macrophages cocultured with H. pylori. The time course of apoptosis matched those of both arginase and iNOS activities. Surprisingly, apoptosis was blocked by the arginase inhibitors Nω-hydroxy-l-arginine or Nω-hydroxy-nor-l-arginine, but not by the iNOS inhibitor N-iminoethyl-l-lysine. These findings were confirmed in peritoneal macrophages from iNOS-deficient mice and were not dependent on bacterial-macrophage contact. Ornithine decarboxylase (ODC), which metabolizes l-ornithine to polyamines, was also induced in H. pylori-stimulated macrophages. Apoptosis was abolished by inhibition of ODC and was restored by the polyamines spermidine and spermine. We also demonstrate that arginase II expression is up-regulated in both murine and human H. pylori gastritis tissues, indicating the likely in vivo relevance of our findings. Therefore, we describe arginase- and ODC-dependent macrophage apoptosis, which implicates polyamines in the pathophysiology of H. pylori infection.

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Section: Discussionmentioning

confidence: 99%

Helicobacter pylori Induces Macrophage Apoptosis by Activation of Arginase II

Gobert

Cheng

Wang

et al. 2002

The Journal of Immunology

157

201

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“…Both the ureaseand amidase-enzymatic reactions lead to the production of ammonia, but although the urease reaction results in alkalinization of the environment (39), the amidase reaction is pHneutral (13,14). Amidase-generated ammonia is probably not sufficient for acid resistance of H. pylori (44) but may still be used to form urea through the previously suggested urea cycle of H. pylori (12,45), and thus, amidase activity may be important when urea availability is low. Alternatively, because ammonia also plays an important role in nitrogen metabolism, the pH-neutral production of ammonia by both amidases may allow the production of sufficient intracellular concentrations of ammonia without alkalinization of the cellular environment.…”

Section: Figmentioning

confidence: 99%

Differential Regulation of Amidase- and Formamidase-mediated Ammonia Production by the Helicobacter pylori Fur Repressor

Vliet¹,

Stoof²,

Poppelaars³

et al. 2003

Journal of Biological Chemistry

130

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The production of high levels of ammonia allows the human gastric pathogen Helicobacter pylori to survive the acidic conditions in the human stomach. H. pylori produces ammonia through urease-mediated degradation of urea, but it is also able to convert a range of amide substrates into ammonia via its AmiE amidase and AmiF formamidase enzymes. Here data are provided that demonstrate that the iron-responsive regulatory protein Fur directly and indirectly regulates the activity of the two H. pylori amidases. In contrast to other amidase-positive bacteria, amidase and formamidase enzyme activities were not induced by medium supplementation with their respective substrates, acrylamide and formamide. AmiE protein expression and amidase enzyme activity were iron-repressed in H. pylori 26695 but constitutive in the isogenic fur mutant. This regulation was mediated at the transcriptional level via the binding of Fur to the amiE promoter region. In contrast, formamidase enzyme activity was not iron-repressed but was significantly higher in the fur mutant. This effect was not mediated at the transcriptional level, and Fur did not bind to the amiF promoter region. These roles of Fur in regulation of the H. pylori amidases suggest that the H. pylori Fur regulator may have acquired extra functions to compensate for the absence of other regulatory systems.The human pathogen Helicobacter pylori colonizes the mucus layer overlaying the gastric epithelium, thereby causing persistent gastritis, which can develop into peptic ulcer disease and gastric carcinomas (1). H. pylori is able to survive and colonize this hostile acidic niche, aided by the expression of its acid resistance mechanisms (2, 3). One of the major factors contributing to acid resistance of H. pylori is the production of ammonia by its urease enzyme, which is essential for gastric colonization in different animal models (4 -7). However, the role of urease in gastric colonization extends beyond protection against gastric acid, because H. pylori urease mutants are still unable to colonize the gastric mucosa when gastric acid production is abolished with proton pump inhibitors (4).Ammonia is a key component of bacterial nitrogen metabolism, because it is the preferred source of nitrogen for the synthesis of amino acids, pyrimidines, and purines. Ammonia plays a central role in pathogenesis and metabolism of the important human pathogen H. pylori, because it not only serves as nitrogen source (8) but also contributes to epithelial cell damage and apoptosis (9, 10), is involved in chemotactic motility (11), and is required for acid resistance (2, 3). Urea is thought to be the main source of ammonia in the gastric environment, but H. pylori does have alternative pathways for the production of ammonia via amino acid catabolism (12) and via the activity of its two paralogous amidases, AmiE 1 and AmiF (13, 14). Aliphatic amidase (AmiE, EC 3.5.1.4) and formamidase (AmiF, EC 3.5.1.49) catalyze the conversion of amide substrates to the corresponding carboxylic acid and ammonia...

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“…A urea cycle in prokaryotes is unusual and is required for removal of ammonia from cells in which toxic intracellular concentrations are likely to occur, such as those of species that carry out rapid amino acid catabolism (Mendz & Hazell, 1996). Sensitivity to ammonia concentration and presence of a urea cycle may, therefore, be linked.…”

Section: Effect Of Ammonium Chloride Concentrationmentioning

confidence: 99%

Manipulation of the physiology of clavulanic acid production in Streptomyces clavuligerus

Ives

Bushell

1997

Microbiology

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~This paper reports a novel use of cluster analysis for the identification of intermediary metabolites that are produced at rates closely correlated with those of antibiotic biosynthesis. This information was used to devise culture feeds resulting in enhanced production of clavulanic acid, an antibiotic of current worldwide commercial interest. The feeding strategies apparently alleviated a rate-limiting supply of the C, precursor of clavulanic acid. C, limitation may be a consequence of unusual nitrogen and carbon metabolism in Streptomyces clawuligenrs. This approach has potential as a generic method for influencing biosynthetic pathway fluxes using feeds without knowledge of the biosynthetic pathway.

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The urea cycle of Helicobacter pylori

Cited by 79 publications

References 19 publications

Helicobacter pylori Induces Macrophage Apoptosis by Activation of Arginase II

Helicobacter pylori Induces Macrophage Apoptosis by Activation of Arginase II

Differential Regulation of Amidase- and Formamidase-mediated Ammonia Production by the Helicobacter pylori Fur Repressor

Manipulation of the physiology of clavulanic acid production in Streptomyces clavuligerus

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