Purine metabolism and the microaerophily of Helicobacter pylori
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© Springer-Verlag 1997
O R I G I N A L PA P E R
George L. Mendz · Andrew J. Shepley · Stuart L. Hazell · Mark A. Smith
Purine metabolism and the microaerophily of Helicobacter pylori
Received: 23 May 1997 / Accepted: 17 July 1997
Abstract The requirements for purine nucleotide synthesis, the effects of purine analogues, and the metabolism of adenine in the bacterium Helicobacter pylori were investigated employing cell culture techniques and one-dimensional NMR spectroscopy. Bacterial cells grew and proliferated in media lacking preformed purines, indicating that H. pylori can synthesize purine nucleotides de novo to meet its requirements. Blocking of this pathway in the absence of sufficient preformed purines for salvage nucleotide synthesis led to cell death. Analogues of purine nucleobases and nucleosides taken up by the cells were cytotoxic, suggesting that salvage routes could be exploited for therapy. Adenine or hypoxanthine were able to substitute for catalase in supporting cell growth and proliferation, suggesting a role for these bases in maintaining the microaerophilic conditions essentially required by the bacterium. Key words Purine biosynthesis · Adenine · Purine analogues · Adenine deaminase · 1H-NMR spectroscopy · Helicobacter pylori · Microaerophily
Introduction The physiology of the bacterium Helicobacter pylori is the subject of active investigation owing to its unique ecological niche and pathogenicity in humans. The genus Helicobacter comprises at present twelve different species of gram-negative, microaerophilic, vibrioid bacteria with
G. L. Mendz (Y) · A. J. Shepley · M. A. Smith School of Biochemistry and Molecular Genetics, School of Microbiology and Immunology, The University of New South Wales, Sydney, N.S.W. 2052, Australia Tel. +61-2-9385-2042; Fax +61-2-9385-1483 e-mail: [email protected] S. L. Hazell School of Microbiology and Immunology, The University of New South Wales, Sydney, N.S.W. 2052, Australia
unique habitats in the stomach and upper intestine of humans and animals (Lee 1989; O’Rourke et al. 1992; Eaton et al. 1993; Stanley et al. 1994). H. pylori is an agent of several gastric diseases including active chronic gastritis (Goodwin et al. 1986; Morris and Nicholson 1987), peptic ulcer disease (Graham 1991), and cancer (Vanzanten and Sherman 1994; International Agency Cancer Research 1994). Although the utilization of basic nutrients and some aspects of the intermediate metabolism of the bacterium have been clarified (Mendz and Hazell 1993, 1995; Mendz et al. 1993, 1994a; Nedenskov 1994), most of the physiology of H. pylori remains unknown. In particular, there is a paucity of information regarding its nucleotide metabolism. The bacterium can synthesize pyrimidine nucleotides de novo and is capable of salvaging preformed pyrimidines (Mendz et al. 1994b). H. pylori is able to salvage purine nucleotide precursors and possesses enzymes involved in purine nucleotide salvage (Mendz et al. 1994c). In a study of the basic nutrients required by the bacterium, Reynolds and Penn (1
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