Metabolism of glutamine and glutathione via γ‐glutamyltranspeptidase and glutamate transport in <i>Helicobacter pylori</i>: possible significance in the pathophysiology of the organism

Shibayama, Keigo; Wachino, Jun-ichi; Arakawa, Yoshichika; Saidijam, Massoud; Rutherford, Nicholas G.; Henderson, Peter J. F.

doi:10.1111/j.1365-2958.2007.05661.x

Cited by 106 publications

(99 citation statements)

References 42 publications

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“…No specific carriers of these amino acids have been characterized in H. pylori. A previous study showed that the uptake of Gln and Glu is carried out by an unknown sodium-dependent transporter (49). We found that gltS (hp1506), annotated to exhibit homology to Na ϩ /Glu symporters, is a good candidate for glutamate uptake in H. pylori.…”

Section: Resultsmentioning

confidence: 99%

“…Purified Hp-␥GT disturbed the proliferation of gastric cells by upregulating growth factors (10), inducing mitochondria-mediated apoptosis (29), and inhibiting T-cell proliferation (45). In H. pylori, both Glu and Gln transport were shown to depend on sodium ions, and the latter additionally on Hp-␥GT activity (48,49).…”

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confidence: 99%

“…The procedure is adapted from that used by Shibayama et al (49). H. pylori parental strains and the isogenic knockout single or double mutants were grown under the same standardized conditions as those used for the enzymatic assays described above.…”

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confidence: 99%

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Coupled Amino Acid Deamidase-Transport Systems Essential for Helicobacter pylori Colonization

et al. 2010

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In addition to their classical roles as carbon or nitrogen sources, amino acids can be used for bacterial virulence, colonization, or stress resistance. We found that original deamidase-transport systems impact colonization by Helicobacter pylori, a human pathogen associated with gastric pathologies, including adenocarcinoma. We demonstrated that L-asparaginase (Hp-AnsB) and ␥-glutamyltranspeptidase (Hp-␥GT) are highly active periplasmic deamidases in H. pylori, producing ammonia and aspartate or glutamate from asparagine and glutamine, respectively. Hp-GltS was identified as a sole and specialized transporter for glutamate, while aspartate was exclusively imported by Hp-DcuA. Uptake of Gln and Asn strictly relies on indirect pathways following prior periplasmic deamidation into Glu and Asp. Hence, in H. pylori, the coupled action of periplasmic deamidases with their respective transporters enables the acquisition of Glu and Asp from Gln and Asn, respectively. These systems were active at neutral rather than acidic pH, suggesting their function near the host epithelial cells. We showed that Hp-DcuA, the fourth component of these novel deamidase-transport systems, was as crucial as Hp-␥GT, Hp-AnsB, and Hp-GltS for animal model colonization. In conclusion, the pH-regulated coupled amino acid deamidase-uptake system represents an original optimized system that is essential for in vivo colonization of the stomach environment by H. pylori. We propose a model in which these two nonredundant systems participate in H. pylori virulence by depleting gastric or immune cells from protective amino acids such as Gln and producing toxic ammonia close to the host cells.

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confidence: 99%

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Coupled Amino Acid Deamidase-Transport Systems Essential for Helicobacter pylori Colonization

et al. 2010

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“…In order to further examine a connection between urea hydrolysis and ammonium metabolism in H. pylori, we considered two of the enzymes in H. pylori that produce rather than assimilate ammonium. Glutaminase (Ggt; encoded by hp1118), and asparaginase (AsnB; encoded by hp0723) are periplasmic enzymes that hydrolyze glutamine and asparagine, respectively, to liberate ammonia (26,(34)(35)(36). Gln and Asn are the major products of the assimilation of urea nitrogen by H. pylori (20).…”

Section: Resultsmentioning

confidence: 99%

Ammonium Metabolism Enzymes Aid Helicobacter pylori Acid Resistance

Miller

Maier

2014

J Bacteriol

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The gastric pathogen Helicobacter pylori possesses a highly active urease to support acid tolerance. Urea hydrolysis occurs inside the cytoplasm, resulting in the production of NH 3 that is immediately protonated to form NH 4 ؉ . This ammonium must be metabolized or effluxed because its presence within the cell is counterproductive to the goal of raising pH while maintaining a viable proton motive force (PMF). Two compatible hypotheses for mitigating intracellular ammonium toxicity include (i) the exit of protonated ammonium outward via the UreI permease, which was shown to facilitate diffusion of both urea and ammonium, and/or (ii) the assimilation of this ammonium, which is supported by evidence that H. pylori assimilates urea nitrogen into its amino acid pools. We investigated the second hypothesis by constructing strains with altered expression of the ammonium-assimilating enzymes glutamine synthetase (GS) and glutamate dehydrogenase (GDH) and the ammonium-evolving periplasmic enzymes glutaminase (Ggt) and asparaginase (AsnB). H. pylori strains expressing elevated levels of either GS or GDH are more acid tolerant than the wild type, exhibit enhanced ammonium production, and are able to alkalize the medium faster than the wild type. Strains lacking the genes for either Ggt or AsnB are acid sensitive, have 8-fold-lower urea-dependent ammonium production, and are more acid sensitive than the parent. Additionally, we found that purified H. pylori GS produces glutamine in the presence of Mg 2؉ at a rate similar to that of unadenylated Escherichia coli GS. These data reveal that all four enzymes contribute to whole-cell acid resistance in H. pylori and are likely important for assimilation and/or efflux of urea-derived ammonium.

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“…gGT catalyzes the hydrolysis and transpeptidation of g-glutamyl compounds such as oxidized and reduced glutathione (9). Another well-known substrate of H. pylori gGT is glutamine, which can be hydrolyzed to glutamate and ammonia (10). Both amino acids have been shown to be important immunomodulators.…”

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Helicobacter pylori γ-Glutamyltranspeptidase Induces Tolerogenic Human Dendritic Cells by Activation of Glutamate Receptors

Käbisch

Semper

Wüstner

et al. 2016

The Journal of Immunology

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Helicobacter pylori infection is characterized by chronic persistence of the bacterium. Different virulence factors, including H. pylori γ-glutamyltranspeptidase (gGT), have been reported to induce tolerogenicity by reprogramming dendritic cells (DCs). gGT is present in all bacterial isolates, indicating an important role for gGT in the course of infection. In the current study, we have analyzed the effect of H. pylori gGT on human DCs and the subsequent adaptive immune response. We show that glutamate produced due to H. pylori gGT enzymatic activity tolerizes DCs by inhibiting cAMP signaling and dampening IL-6 secretion in response to the infection. Together, our results provide a novel molecular mechanism by which H. pylori manipulates the host’s immune response to persist within its host.

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Metabolism of glutamine and glutathione via γ‐glutamyltranspeptidase and glutamate transport in Helicobacter pylori: possible significance in the pathophysiology of the organism

Cited by 106 publications

References 42 publications

Coupled Amino Acid Deamidase-Transport Systems Essential for Helicobacter pylori Colonization

Coupled Amino Acid Deamidase-Transport Systems Essential for Helicobacter pylori Colonization

Ammonium Metabolism Enzymes Aid Helicobacter pylori Acid Resistance

Helicobacter pylori γ-Glutamyltranspeptidase Induces Tolerogenic Human Dendritic Cells by Activation of Glutamate Receptors

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