Purine metabolism and the microaerophily of Helicobacter pylori

Mendz, George L.; Shepley, Andrew; Hazell, Stuart L.; Smith, Mark A.

doi:10.1007/s002030050521

Cited by 19 publications

(29 citation statements)

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“…Purine salvage and utilization have previously been examined in H. pylori (18,49,50). Radiolabeling studies have been used to show uptake and incorporation of the purine bases adenine and guanine (and to a lesser extent, hypoxanthine) (50).…”

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“…The presence of adenine, guanine, and hypoxanthine phosphoribosyltransferase activities have been measured from whole-cell lysates (50), and an in-depth look at the enzymatic nature of H. pylori's purified xanthine-guanine phosphoribosyltransferase demonstrated its ability to catalyze the formation of 6-oxopurines (18). One study has shown that H. pylori can grow in the absence of preformed purines as long as exogenous catalase is present (49). It has been shown that exogenous catalase added to medium can increase the growth of H. pylori by preventing the formation of toxic peroxidation products from unsaturated fatty acids (29) and that bovine serum albumin (BSA) and catalase together can provide the minimal requirements by which H. pylori can grow on blood-or serum-free media (30).…”

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confidence: 99%

“…It has been shown that exogenous catalase added to medium can increase the growth of H. pylori by preventing the formation of toxic peroxidation products from unsaturated fatty acids (29) and that bovine serum albumin (BSA) and catalase together can provide the minimal requirements by which H. pylori can grow on blood-or serum-free media (30). Regarding growth in the absence of purines, the hypothesis is that in H. pylori, de novo purine nucleotide biosynthesis requires H. pylori to perform at its metabolic peak, and only when exogenous catalase is present can it achieve that threshold (49). However, since these initial findings, sequence analysis of the genome indicates that H. pylori lacks most of the enzymatic machinery believed to be required for classical de novo purine nucleotide biosynthesis (Fig.…”

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Helicobacter pylori Relies Primarily on the Purine Salvage Pathway for Purine Nucleotide Biosynthesis

Liechti

Goldberg

2012

J Bacteriol

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Helicobacter pylori is a chronic colonizer of the gastric epithelium and plays a major role in the development of gastritis, peptic ulcer disease, and gastric cancer. In its coevolution with humans, the streamlining of the H. pylori genome has resulted in a significant reduction in metabolic pathways, one being purine nucleotide biosynthesis. Bioinformatic analysis has revealed that H. pylori lacks the enzymatic machinery for de novo production of IMP, the first purine nucleotide formed during GTP and ATP biosynthesis. This suggests that H. pylori must rely heavily on salvage of purines from the environment. In this study, we deleted several genes putatively involved in purine salvage and processing. The growth and survival of these mutants were analyzed in both nutrient-rich and minimal media, and the results confirmed the presence of a robust purine salvage pathway in H. pylori. Of the two phosphoribosyltransferase genes found in the H. pylori genome, only gpt appears to be essential, and an ⌬apt mutant strain was still capable of growth on adenine, suggesting that adenine processing via Apt is not essential. Deletion of the putative nucleoside phosphorylase gene deoD resulted in an inability of H. pylori to grow on purine nucleosides or the purine base adenine. Our results suggest a purine requirement for growth of H. pylori in standard media, indicating that H. pylori possesses the ability to utilize purines and nucleosides from the environment in the absence of a de novo purine nucleotide biosynthesis pathway. Helicobacter pylori is a Gram-negative, microaerophilic helixshaped bacterium that colonizes the gastric mucosa of roughly half of the world's population (19,53). Unlike numerous other pathogenic bacteria capable of existing in diverse environmental niches, H. pylori is only capable of sustained growth within its human host (19). Identified only 27 years ago (45), this bacterium was the first to have two different strains sequenced, allowing for the first genome-wide comparative bioinformatic analysis of a bacterial species (1, 16). The results of this comparative sequencing project (16) as well as subsequent sequencing projects (3) show a relatively small genome with numerous alterations in its metabolic pathways compared with those of other bacterial species. Initial conclusions were that the missing pathway enzymes simply were divergent enough to escape classification by homology screening (16); however, subsequent analysis of the genome has identified 48 potential "dead-end metabolites" (metabolites only consumed or only produced within a metabolic network), indicating missing knowledge about a particular pathway or absence of a fully functional pathway (67). One hypothesis developed to explain these abnormalities was that, having evolved alongside humans for so long, the metabolism of H. pylori was streamlined to coexist in the human niche. Apparent holes in the metabolic pathways of H. pylori suggest the loss of genes no longer required for growth in its relatively stable environment of the huma...

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Helicobacter pylori Relies Primarily on the Purine Salvage Pathway for Purine Nucleotide Biosynthesis

Liechti

Goldberg

2012

J Bacteriol

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“…Adenine is the most prominent purine in the blood (22), and of all the purine bases, it has been shown to be the most rapidly taken up and processed into nucleotides by H. pylori (43). All these findings, including the more recent discovery of adenosine deaminase activity in at least three H. pylori strains (16,17,20), have pointed to adenine/adenosine being the prominent purine base/nucleoside utilized by this bacterium. However, recently an H. pylori ⌬guaA mutant was shown to have no colonization defects in a murine model of infection (20).…”

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“…When grown in a defined medium derived by Reynolds and Penn (termed RnP medium) (15), purines were initially shown to be required for growth in strain NCTC 11637 as well as in eight clinical isolates. A subsequent study, however, reported that growth could be achieved in the absence of purines if the medium was supplemented with 0.1% catalase in strains NCTC 11639 and N6 and two low-passage-number clinical isolates (16). It was more recently shown that purines are required for growth in Reynolds and Penn's defined medium for strain G27 (17), and that catalase was incapable of restoring growth in purine-free media.…”

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Helicobacter pylori Salvages Purines from Extracellular Host Cell DNA Utilizing the Outer Membrane-Associated Nuclease NucT

Liechti

Goldberg

2013

J Bacteriol

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Helicobacter pylori is a bacterial pathogen that establishes life-long infections in humans, and its presence in the gastric epithelium is strongly associated with gastritis, peptic ulcer disease, and gastric cancer. Having evolved in this specific gastric niche for hundreds of thousands of years, this microbe has become dependent on its human host. Bioinformatic analysis reveals that H. pylori has lost several genes involved in the de novo synthesis of purine nucleotides, and without this pathway present, H. pylori must salvage purines from its environment in order to grow. While the presence and abundance of free purines in various mammalian tissues has been loosely quantified, the concentration of purines present within the gastric mucosa remains unknown. There is evidence, however, that a significant amount of extracellular DNA is present in the human gastric mucosal layer as a result of epithelial cell turnover, and this DNA has the potential to serve as an adequate purine source for gastric purine auxotrophs. In this study, we characterize the ability of H. pylori to grow utilizing only DNA as a purine source. We show that this ability is independent of the ComB DNA uptake system, and that H. pylori utilization of DNA as a purine source is largely influenced by the presence of an outer membrane-associated nuclease (NucT). A ⌬nucT mutant exhibits significantly reduced extracellular nuclease activity and is deficient in growth when DNA is provided as the sole purine source in laboratory growth media. These growth defects are also evident when this nuclease mutant is grown in the presence of AGS cells or in purine-free tissue culture medium that has been conditioned by AGS cells in the absence of fetal bovine serum. Taken together, these results indicate that the salvage of purines from exogenous host cell DNA plays an important role in allowing H. pylori to meet its purine requirements for growth.

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Helicobacter pylori

Posteraro

Sanguinetti

2015

Molecular Medical Microbiology

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Purine metabolism and the microaerophily of Helicobacter pylori

Cited by 19 publications

References 19 publications

Helicobacter pylori Relies Primarily on the Purine Salvage Pathway for Purine Nucleotide Biosynthesis

Helicobacter pylori Relies Primarily on the Purine Salvage Pathway for Purine Nucleotide Biosynthesis

Helicobacter pylori Salvages Purines from Extracellular Host Cell DNA Utilizing the Outer Membrane-Associated Nuclease NucT

Helicobacter pylori

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