{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T01:02:24Z","timestamp":1794445344303,"version":"4.9.1"},"reference-count":86,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2002,5,21]],"date-time":"2002-05-21T00:00:00Z","timestamp":1021939200000},"content-version":"vor","delay-in-days":719,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Microbiology"],"published-print":{"date-parts":[[2000,6]]},"abstract":"<jats:p>NRAMPs (natural resistance\u2010associated macrophage proteins) have been characterized in mammals as divalent transition metal transporters involved in iron metabolism and host resistance to certain pathogens. The mechanism of pathogen resistance is proposed to involve sequestration of Fe<jats:sup>2+<\/jats:sup> and Mn<jats:sup>2+<\/jats:sup>, cofactors of both prokaryotic and eukaryotic catalases and superoxide dismutases, not only to protect the macrophage against its own generation of reactive oxygen species, but to deny the cations to the pathogen for synthesis of its protective enzymes. NRAMP homologues are also present in bacteria. We report the cloning and characterization of the single NRAMP genes in <jats:italic>Escherichia coli<\/jats:italic> and <jats:italic>Salmonella enterica<\/jats:italic> ssp. <jats:italic>typhimurium<\/jats:italic>, and the cloning of two distinct NRAMP genes from <jats:italic>Pseudomonas aeruginosa<\/jats:italic> and an internal fragment of an NRAMP gene in <jats:italic>Burkholderia cepacia<\/jats:italic>. The genes are designated <jats:italic>mntH<\/jats:italic> because the two enterobacterial NRAMPs encode H<jats:sup>+<\/jats:sup>\u2010stimulated, highly selective manganese(II) transport systems, accounting for all Mn<jats:sup>2+<\/jats:sup> uptake in each species under the conditions tested. For <jats:italic>S. typhimurium<\/jats:italic> MntH, the <jats:italic>K<\/jats:italic><jats:sub>m<\/jats:sub> for <jats:sup>54<\/jats:sup>Mn<jats:sup>2+<\/jats:sup> (\u2248\u20030.1\u2003\u00b5M) was pH independent, but maximal uptake increased as pH decreased. Monovalent cations, osmotic strength, Mg<jats:sup>2+<\/jats:sup> and Ca<jats:sup>2+<\/jats:sup> did not inhibit <jats:sup>54<\/jats:sup>Mn<jats:sup>2+<\/jats:sup> uptake. Ni<jats:sup>2+<\/jats:sup>, Cu<jats:sup>2+<\/jats:sup> and Zn<jats:sup>2+<\/jats:sup> inhibited uptake with <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>s greater than 100\u2003\u00b5M, Co<jats:sup>2+<\/jats:sup> with a <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> of 20\u2003\u00b5M and Fe<jats:sup>2+<\/jats:sup> with a <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> that decreased from 100\u2003\u00b5M at pH\u20037.6 to 10\u2003\u00b5M at pH\u20035.5. Fe<jats:sup>3+<\/jats:sup> and Pb<jats:sup>2+<\/jats:sup> inhibited weakly, exhibiting <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>s of 50\u2003\u00b5M, while Cd<jats:sup>2+<\/jats:sup> was a potent inhibitor with a <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> of about 1\u2003\u00b5M. <jats:italic>E. coli<\/jats:italic> MntH had a similar inhibition profile, except that <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>s were three\u2010 to 10\u2010fold higher. Both <jats:italic>S. typhimurium<\/jats:italic> and <jats:italic>E. coli<\/jats:italic> MntH also transport <jats:sup>55<\/jats:sup>Fe<jats:sup>2+<\/jats:sup> however, the <jats:italic>K<\/jats:italic><jats:sub>m<\/jats:sub>s are equivalent to the <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>s for Fe<jats:sup>2+<\/jats:sup> inhibition of Mn<jats:sup>2+<\/jats:sup> uptake, and are thus too high to be physiologically relevant. In both <jats:italic>S. typhimurium and E. coli<\/jats:italic>, <jats:italic>mntH<\/jats:italic>::<jats:italic>lacZ<\/jats:italic> constructs were strongly induced by hydrogen peroxide, weakly induced by EDTA and unresponsive to paraquat, consistent with the presence of Fur and OxyR binding sites in the promoters. Strains overexpressing <jats:italic>mntH<\/jats:italic> were more susceptible to growth inhibition by Mn<jats:sup>2+<\/jats:sup> and Cd<jats:sup>2+<\/jats:sup> than wild type, and strains lacking a functional <jats:italic>mntH<\/jats:italic> gene were more susceptible to killing by hydrogen peroxide. In <jats:italic>S. typhimurium<\/jats:italic> strain SL1344, <jats:italic>mntH<\/jats:italic> mutants showed no defect in invasion of or survival in cultured HeLa or RAW264.7 macrophage cells; however, expression of <jats:italic>mntH<\/jats:italic>::<jats:italic>lacZ<\/jats:italic> was induced severalfold by 3\u2003h after invasion of the macrophages. <jats:italic>S. typhimurium mntH<\/jats:italic> mutants showed only a slight attenuation of virulence in BALB\/c mice. Thus, the NRAMP Mn<jats:sup>2+<\/jats:sup> transporter MntH and Mn<jats:sup>2+<\/jats:sup> play a role in bacterial response to reactive oxygen species and possibly have a role in pathogenesis.<\/jats:p>","DOI":"10.1046\/j.1365-2958.2000.01922.x","type":"journal-article","created":{"date-parts":[[2003,3,12]],"date-time":"2003-03-12T11:31:02Z","timestamp":1047468662000},"page":"1085-1100","source":"Crossref","is-referenced-by-count":266,"title":["The NRAMP proteins of <i>Salmonella typhimurium<\/i> and <i>Escherichia coli<\/i> are selective manganese transporters involved in the response to reactive oxygen"],"prefix":"10.1111","volume":"36","author":[{"given":"David G.","family":"Kehres","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle L.","family":"Zaharik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. 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