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<!DOCTYPE html> <html lang="en" class="no-js"> <head> <meta charset="UTF-8"> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="applicable-device" content="pc,mobile"> <meta name="viewport" content="width=device-width, initial-scale=1"> <title>Acidithiobacillus ferrooxidans metabolism: from genome sequence to industrial applications | BMC Genomics | Full Text</title> <meta name="citation_abstract" content="Acidithiobacillus ferrooxidans is a major participant in consortia of microorganisms used for the industrial recovery of copper (bioleaching or biomining). It is a chemolithoautrophic, γ-proteobacterium using energy from the oxidation of iron- and sulfur-containing minerals for growth. It thrives at extremely low pH (pH 1–2) and fixes both carbon and nitrogen from the atmosphere. It solubilizes copper and other metals from rocks and plays an important role in nutrient and metal biogeochemical cycling in acid environments. The lack of a well-developed system for genetic manipulation has prevented thorough exploration of its physiology. Also, confusion has been caused by prior metabolic models constructed based upon the examination of multiple, and sometimes distantly related, strains of the microorganism. The genome of the type strain A. ferrooxidans ATCC 23270 was sequenced and annotated to identify general features and provide a framework for in silico metabolic reconstruction. Earlier models of iron and sulfur oxidation, biofilm formation, quorum sensing, inorganic ion uptake, and amino acid metabolism are confirmed and extended. Initial models are presented for central carbon metabolism, anaerobic metabolism (including sulfur reduction, hydrogen metabolism and nitrogen fixation), stress responses, DNA repair, and metal and toxic compound fluxes. Bioinformatics analysis provides a valuable platform for gene discovery and functional prediction that helps explain the activity of A. ferrooxidans in industrial bioleaching and its role as a primary producer in acidic environments. An analysis of the genome of the type strain provides a coherent view of its gene content and metabolic potential."/> <meta name="journal_id" content="12864"/> <meta name="dc.title" content="Acidithiobacillus ferrooxidans metabolism: from genome sequence to industrial applications"/> <meta name="dc.source" content="BMC Genomics 2008 9:1"/> <meta name="dc.format" content="text/html"/> <meta name="dc.publisher" content="BioMed Central"/> <meta name="dc.date" content="2008-12-11"/> <meta name="dc.type" content="OriginalPaper"/> <meta name="dc.language" content="En"/> <meta name="dc.copyright" content="2008 Valdés et al; licensee BioMed Central Ltd."/> <meta name="dc.rights" content="http://creativecommons.org/licenses/by/2.0"/> <meta name="dc.rightsAgent" content="reprints@biomedcentral.com"/> <meta name="dc.description" content="Acidithiobacillus ferrooxidans is a major participant in consortia of microorganisms used for the industrial recovery of copper (bioleaching or biomining). It is a chemolithoautrophic, γ-proteobacterium using energy from the oxidation of iron- and sulfur-containing minerals for growth. It thrives at extremely low pH (pH 1–2) and fixes both carbon and nitrogen from the atmosphere. It solubilizes copper and other metals from rocks and plays an important role in nutrient and metal biogeochemical cycling in acid environments. The lack of a well-developed system for genetic manipulation has prevented thorough exploration of its physiology. Also, confusion has been caused by prior metabolic models constructed based upon the examination of multiple, and sometimes distantly related, strains of the microorganism. The genome of the type strain A. ferrooxidans ATCC 23270 was sequenced and annotated to identify general features and provide a framework for in silico metabolic reconstruction. Earlier models of iron and sulfur oxidation, biofilm formation, quorum sensing, inorganic ion uptake, and amino acid metabolism are confirmed and extended. Initial models are presented for central carbon metabolism, anaerobic metabolism (including sulfur reduction, hydrogen metabolism and nitrogen fixation), stress responses, DNA repair, and metal and toxic compound fluxes. Bioinformatics analysis provides a valuable platform for gene discovery and functional prediction that helps explain the activity of A. ferrooxidans in industrial bioleaching and its role as a primary producer in acidic environments. An analysis of the genome of the type strain provides a coherent view of its gene content and metabolic potential."/> <meta name="prism.issn" content="1471-2164"/> <meta name="prism.publicationName" content="BMC Genomics"/> <meta name="prism.publicationDate" content="2008-12-11"/> <meta name="prism.volume" content="9"/> <meta name="prism.number" content="1"/> <meta name="prism.section" content="OriginalPaper"/> <meta name="prism.startingPage" content="1"/> <meta name="prism.endingPage" content="24"/> <meta name="prism.copyright" content="2008 Valdés et al; licensee BioMed Central Ltd."/> <meta name="prism.rightsAgent" content="reprints@biomedcentral.com"/> <meta name="prism.url" content="https://bmcgenomics.biomedcentral.com/articles/10.1186/1471-2164-9-597"/> <meta name="prism.doi" content="doi:10.1186/1471-2164-9-597"/> <meta name="citation_pdf_url" content="https://bmcgenomics.biomedcentral.com/counter/pdf/10.1186/1471-2164-9-597"/> <meta name="citation_fulltext_html_url" content="https://bmcgenomics.biomedcentral.com/articles/10.1186/1471-2164-9-597"/> <meta name="citation_journal_title" content="BMC Genomics"/> <meta name="citation_journal_abbrev" content="BMC Genomics"/> <meta name="citation_publisher" content="BioMed Central"/> <meta name="citation_issn" content="1471-2164"/> <meta name="citation_title" content="Acidithiobacillus ferrooxidans metabolism: from genome sequence to industrial applications"/> <meta name="citation_volume" content="9"/> <meta name="citation_issue" content="1"/> <meta name="citation_publication_date" content="2008/12"/> <meta name="citation_online_date" content="2008/12/11"/> <meta name="citation_firstpage" content="1"/> <meta name="citation_lastpage" content="24"/> <meta name="citation_article_type" content="Research article"/> <meta name="citation_fulltext_world_readable" content=""/> <meta name="citation_language" content="en"/> <meta name="dc.identifier" content="doi:10.1186/1471-2164-9-597"/> <meta name="DOI" content="10.1186/1471-2164-9-597"/> <meta name="size" content="402725"/> <meta name="citation_doi" content="10.1186/1471-2164-9-597"/> <meta name="citation_springer_api_url" content="http://api.springer.com/xmldata/jats?q=doi:10.1186/1471-2164-9-597&api_key="/> <meta name="description" content="Acidithiobacillus ferrooxidans is a major participant in consortia of microorganisms used for the industrial recovery of copper (bioleaching or biomining). It is a chemolithoautrophic, γ-proteobacterium using energy from the oxidation of iron- and sulfur-containing minerals for growth. It thrives at extremely low pH (pH 1–2) and fixes both carbon and nitrogen from the atmosphere. It solubilizes copper and other metals from rocks and plays an important role in nutrient and metal biogeochemical cycling in acid environments. The lack of a well-developed system for genetic manipulation has prevented thorough exploration of its physiology. Also, confusion has been caused by prior metabolic models constructed based upon the examination of multiple, and sometimes distantly related, strains of the microorganism. The genome of the type strain A. ferrooxidans ATCC 23270 was sequenced and annotated to identify general features and provide a framework for in silico metabolic reconstruction. Earlier models of iron and sulfur oxidation, biofilm formation, quorum sensing, inorganic ion uptake, and amino acid metabolism are confirmed and extended. Initial models are presented for central carbon metabolism, anaerobic metabolism (including sulfur reduction, hydrogen metabolism and nitrogen fixation), stress responses, DNA repair, and metal and toxic compound fluxes. Bioinformatics analysis provides a valuable platform for gene discovery and functional prediction that helps explain the activity of A. ferrooxidans in industrial bioleaching and its role as a primary producer in acidic environments. An analysis of the genome of the type strain provides a coherent view of its gene content and metabolic potential."/> <meta name="dc.creator" content="Valdés, Jorge"/> <meta name="dc.creator" content="Pedroso, Inti"/> <meta name="dc.creator" content="Quatrini, Raquel"/> <meta name="dc.creator" content="Dodson, Robert J"/> <meta name="dc.creator" content="Tettelin, Herve"/> <meta name="dc.creator" content="Blake, Robert"/> <meta name="dc.creator" content="Eisen, Jonathan A"/> <meta name="dc.creator" content="Holmes, David S"/> <meta name="dc.subject" content="Life Sciences, general"/> <meta name="dc.subject" content="Microarrays"/> <meta name="dc.subject" content="Proteomics"/> <meta name="dc.subject" content="Animal Genetics and Genomics"/> <meta name="dc.subject" content="Microbial Genetics and Genomics"/> <meta name="dc.subject" content="Plant Genetics and Genomics"/> <meta name="citation_reference" content="citation_journal_title=Appl Microbiol Biotechnol; citation_title=Bioleaching review part A: progress in bioleaching: fundamentals and mechanisms of bacterial metal sulfide oxidation; 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It is a chemolithoautrophic, γ-proteobacterium using energy from the oxidation of iron- and sulfur-containing minerals for growth. It thrives at extremely low pH (pH 1–2) and fixes both carbon and nitrogen from the atmosphere. It solubilizes copper and other metals from rocks and plays an important role in nutrient and metal biogeochemical cycling in acid environments. The lack of a well-developed system for genetic manipulation has prevented thorough exploration of its physiology. Also, confusion has been caused by prior metabolic models constructed based upon the examination of multiple, and sometimes distantly related, strains of the microorganism. Results The genome of the type strain A. ferrooxidans ATCC 23270 was sequenced and annotated to identify general features and provide a framework for in silico metabolic reconstruction. Earlier models of iron and sulfur oxidation, biofilm formation, quorum sensing, inorganic ion uptake, and amino acid metabolism are confirmed and extended. Initial models are presented for central carbon metabolism, anaerobic metabolism (including sulfur reduction, hydrogen metabolism and nitrogen fixation), stress responses, DNA repair, and metal and toxic compound fluxes. Conclusion Bioinformatics analysis provides a valuable platform for gene discovery and functional prediction that helps explain the activity of A. ferrooxidans in industrial bioleaching and its role as a primary producer in acidic environments. An analysis of the genome of the type strain provides a coherent view of its gene content and metabolic potential."/> <meta property="og:image" content="https://static-content.springer.com/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig1_HTML.jpg"/> <script type="application/ld+json">{"mainEntity":{"headline":"Acidithiobacillus ferrooxidans metabolism: from genome sequence to industrial applications","description":"Acidithiobacillus ferrooxidans is a major participant in consortia of microorganisms used for the industrial recovery of copper (bioleaching or biomining). It is a chemolithoautrophic, γ-proteobacterium using energy from the oxidation of iron- and sulfur-containing minerals for growth. It thrives at extremely low pH (pH 1–2) and fixes both carbon and nitrogen from the atmosphere. It solubilizes copper and other metals from rocks and plays an important role in nutrient and metal biogeochemical cycling in acid environments. The lack of a well-developed system for genetic manipulation has prevented thorough exploration of its physiology. Also, confusion has been caused by prior metabolic models constructed based upon the examination of multiple, and sometimes distantly related, strains of the microorganism. The genome of the type strain A. ferrooxidans ATCC 23270 was sequenced and annotated to identify general features and provide a framework for in silico metabolic reconstruction. Earlier models of iron and sulfur oxidation, biofilm formation, quorum sensing, inorganic ion uptake, and amino acid metabolism are confirmed and extended. Initial models are presented for central carbon metabolism, anaerobic metabolism (including sulfur reduction, hydrogen metabolism and nitrogen fixation), stress responses, DNA repair, and metal and toxic compound fluxes. Bioinformatics analysis provides a valuable platform for gene discovery and functional prediction that helps explain the activity of A. ferrooxidans in industrial bioleaching and its role as a primary producer in acidic environments. An analysis of the genome of the type strain provides a coherent view of its gene content and metabolic potential.","datePublished":"2008-12-11T00:00:00Z","dateModified":"2008-12-11T00:00:00Z","pageStart":"1","pageEnd":"24","license":"https://creativecommons.org/licenses/by/2.0","sameAs":"https://doi.org/10.1186/1471-2164-9-597","keywords":["Sulfur Oxidation","Central Carbon Metabolism","Heavy Metal Resistance","Inorganic Sulfur Compound","Reverse Electron Flow","Life Sciences","general","Microarrays","Proteomics","Animal Genetics and Genomics","Microbial Genetics and Genomics","Plant Genetics and Genomics"],"image":["https://media.springernature.com/lw1200/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig1_HTML.jpg","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig2_HTML.jpg","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig6_HTML.jpg","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig7_HTML.jpg"],"isPartOf":{"name":"BMC Genomics","issn":["1471-2164"],"volumeNumber":"9","@type":["Periodical","PublicationVolume"]},"publisher":{"name":"BioMed Central","logo":{"url":"https://www.springernature.com/app-sn/public/images/logo-springernature.png","@type":"ImageObject"},"@type":"Organization"},"author":[{"name":"Jorge Valdés","affiliation":[{"name":"Universidad Andres Bello","address":{"name":"Center for Bioinformatics and Genome Biology, Fundación Ciencia para la Vida and Depto. de Ciencias Biologicas, Facultad de Ciencias de la Salud, Universidad Andres Bello, Santiago, Chile","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Inti Pedroso","affiliation":[{"name":"Universidad Andres Bello","address":{"name":"Center for Bioinformatics and Genome Biology, Fundación Ciencia para la Vida and Depto. de Ciencias Biologicas, Facultad de Ciencias de la Salud, Universidad Andres Bello, Santiago, Chile","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Raquel Quatrini","affiliation":[{"name":"Universidad Andres Bello","address":{"name":"Center for Bioinformatics and Genome Biology, Fundación Ciencia para la Vida and Depto. de Ciencias Biologicas, Facultad de Ciencias de la Salud, Universidad Andres Bello, Santiago, Chile","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Robert J Dodson","affiliation":[{"name":"J. Craig Venter Institute","address":{"name":"J. Craig Venter Institute, Rockville, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Herve Tettelin","affiliation":[{"name":"J. Craig Venter Institute","address":{"name":"J. Craig Venter Institute, Rockville, USA","@type":"PostalAddress"},"@type":"Organization"},{"name":"University of Maryland","address":{"name":"The Institute for Genomic Sciences, University of Maryland, Baltimore, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Robert Blake","affiliation":[{"name":"Xavier University","address":{"name":"Division of Basic Pharmaceutical Sciences, Xavier University, New Orleans, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Jonathan A Eisen","affiliation":[{"name":"J. Craig Venter Institute","address":{"name":"J. Craig Venter Institute, Rockville, USA","@type":"PostalAddress"},"@type":"Organization"},{"name":"University of California Davis Genome Center","address":{"name":"Section of Evolution and Ecology, U.C. Davis, University of California Davis Genome Center, Davis, USA","@type":"PostalAddress"},"@type":"Organization"},{"name":"University of California Davis Genome Center","address":{"name":"Dept of Medical Microbiology and Immunology, U.C. Davis, University of California Davis Genome Center, Davis, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"David S Holmes","affiliation":[{"name":"Universidad Andres Bello","address":{"name":"Center for Bioinformatics and Genome Biology, Fundación Ciencia para la Vida and Depto. de Ciencias Biologicas, Facultad de Ciencias de la Salud, Universidad Andres Bello, Santiago, Chile","@type":"PostalAddress"},"@type":"Organization"}],"email":"dsholmes2000@yahoo.com","@type":"Person"}],"isAccessibleForFree":true,"@type":"ScholarlyArticle"},"@context":"https://schema.org","@type":"WebPage"}</script> </head> <body class="journal journal-fulltext" > <div class="ctm"></div>  <noscript> <iframe src="https://www.googletagmanager.com/ns.html?id=GTM-MRVXSHQ" height="0" width="0" style="display:none;visibility:hidden"></iframe> </noscript>  <div class="u-visually-hidden" aria-hidden="true"> <?xml version="1.0" encoding="UTF-8"?><!DOCTYPE svg PUBLIC "-//W3C//DTD SVG 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download> <span class="c-pdf-download__text">Download PDF</span> <svg aria-hidden="true" focusable="false" width="16" height="16" class="u-icon"><use xlink:href="#icon-download"/></svg> </a> </div> </div> </div> <article lang="en"> <div class="c-article-header"> <ul class="c-article-identifiers" data-test="article-identifier"> <li class="c-article-identifiers__item" data-test="article-category">Research article</li> <li class="c-article-identifiers__item"> <a href="https://www.springernature.com/gp/open-research/about/the-fundamentals-of-open-access-and-open-research" data-track="click" data-track-action="open access" data-track-label="link" class="u-color-open-access" data-test="open-access">Open access</a> </li> <li class="c-article-identifiers__item">Published: <time datetime="2008-12-11">11 December 2008</time></li> </ul> <h1 class="c-article-title" data-test="article-title" data-article-title=""><i>Acidithiobacillus ferrooxidans</i> metabolism: from genome sequence to industrial applications</h1> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Jorge-Vald_s-Aff1" data-author-popup="auth-Jorge-Vald_s-Aff1" data-author-search="Valdés, Jorge">Jorge Valdés</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Inti-Pedroso-Aff1" data-author-popup="auth-Inti-Pedroso-Aff1" data-author-search="Pedroso, Inti">Inti Pedroso</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Raquel-Quatrini-Aff1" data-author-popup="auth-Raquel-Quatrini-Aff1" data-author-search="Quatrini, Raquel">Raquel Quatrini</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Robert_J-Dodson-Aff2" data-author-popup="auth-Robert_J-Dodson-Aff2" data-author-search="Dodson, Robert J">Robert J Dodson</a><sup class="u-js-hide"><a href="#Aff2">2</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Herve-Tettelin-Aff2-Aff3" data-author-popup="auth-Herve-Tettelin-Aff2-Aff3" data-author-search="Tettelin, Herve">Herve Tettelin</a><sup class="u-js-hide"><a href="#Aff2">2</a>,<a href="#Aff3">3</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Robert-Blake-Aff6" data-author-popup="auth-Robert-Blake-Aff6" data-author-search="Blake, Robert">Robert Blake II</a><sup class="u-js-hide"><a href="#Aff6">6</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Jonathan_A-Eisen-Aff2-Aff4-Aff5" data-author-popup="auth-Jonathan_A-Eisen-Aff2-Aff4-Aff5" data-author-search="Eisen, Jonathan A">Jonathan A Eisen</a><sup class="u-js-hide"><a href="#Aff2">2</a>,<a href="#Aff4">4</a>,<a href="#Aff5">5</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 8 authors for this article" title="Show all 8 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-David_S-Holmes-Aff1" data-author-popup="auth-David_S-Holmes-Aff1" data-author-search="Holmes, David S" data-corresp-id="c1">David S Holmes<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">BMC Genomics</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 9</b>, Article number: <span data-test="article-number">597</span> (<span data-test="article-publication-year">2008</span>) <a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">82k <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="citation-count"> <p class="c-article-metrics-bar__count">448 <span class="c-article-metrics-bar__label">Citations</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">18 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/10.1186/1471-2164-9-597/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </div> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Background</h3><p><i>Acidithiobacillus ferrooxidans</i> is a major participant in consortia of microorganisms used for the industrial recovery of copper (bioleaching or biomining). It is a chemolithoautrophic, γ-proteobacterium using energy from the oxidation of iron- and sulfur-containing minerals for growth. It thrives at extremely low pH (pH 1–2) and fixes both carbon and nitrogen from the atmosphere. It solubilizes copper and other metals from rocks and plays an important role in nutrient and metal biogeochemical cycling in acid environments. The lack of a well-developed system for genetic manipulation has prevented thorough exploration of its physiology. Also, confusion has been caused by prior metabolic models constructed based upon the examination of multiple, and sometimes distantly related, strains of the microorganism.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Results</h3><p>The genome of the type strain <i>A. ferrooxidans</i> ATCC 23270 was sequenced and annotated to identify general features and provide a framework for <i>in silico</i> metabolic reconstruction. Earlier models of iron and sulfur oxidation, biofilm formation, quorum sensing, inorganic ion uptake, and amino acid metabolism are confirmed and extended. Initial models are presented for central carbon metabolism, anaerobic metabolism (including sulfur reduction, hydrogen metabolism and nitrogen fixation), stress responses, DNA repair, and metal and toxic compound fluxes.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Conclusion</h3><p>Bioinformatics analysis provides a valuable platform for gene discovery and functional prediction that helps explain the activity of <i>A. ferrooxidans</i> in industrial bioleaching and its role as a primary producer in acidic environments. An analysis of the genome of the type strain provides a coherent view of its gene content and metabolic potential.</p></div></div></section> <section data-title="Background"><div class="c-article-section" id="Sec1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec1">Background</h2><div class="c-article-section__content" id="Sec1-content"><p><i>Acidithiobacillus ferrooxidans</i> is a Gram-negative, γ-proteobacterium that thrives optimally at 30°C and pH 2, but can grow at pH 1 or lower [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Rohwerder T, Gehrke T, Kinzler K, Sand W: Bioleaching review part A: progress in bioleaching: fundamentals and mechanisms of bacterial metal sulfide oxidation. Appl Microbiol Biotechnol. 2003, 63 (3): 239-248. 10.1007/s00253-003-1448-7." href="/articles/10.1186/1471-2164-9-597#ref-CR1" id="ref-link-section-d25988610e586">1</a>]. It is abundant in natural environments associated with pyritic ore bodies, coal deposits, and their acidified drainages [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Gonzalez-Toril E, Llobet-Brossa E, Casamayor EO, Amann R, Amils R: Microbial ecology of an extreme acidic environment, the Tinto River. Appl Environ Microbiol. 2003, 69 (8): 4853-4865. 10.1128/AEM.69.8.4853-4865.2003." href="/articles/10.1186/1471-2164-9-597#ref-CR2" id="ref-link-section-d25988610e589">2</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Davis RA, Welty AT, Borrego J, Morales JA, Pendon JG, Ryan JG: Rio Tinto estuary (Spain): 5000 years of pollution. Environmental Geology. 2000, 39 (10): 1107-1116. 10.1007/s002549900096." href="/articles/10.1186/1471-2164-9-597#ref-CR3" id="ref-link-section-d25988610e592">3</a>]. It is an important member of microbial consortia used to recover copper via a process known as bioleaching or biomining [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Rawlings DE: Heavy metal mining using microbes. Annu Rev Microbiol. 2002, 56: 65-91. 10.1146/annurev.micro.56.012302.161052." href="/articles/10.1186/1471-2164-9-597#ref-CR4" id="ref-link-section-d25988610e595">4</a>].</p><p>In a typical bioleaching operation, copper ore is first pulverized and placed in heaps. The heaps are then sprinkled with sulfuric acid and aerated to promote the microbial oxidation of iron and sulfur compounds. Some bioleaching heaps are very extensive; for example, the Escondida mine in northern Chile is putting into operation a heap that is 5 km long by 2 km wide and 126 m high (David Dew, personal communication). With a volume of a little more than one trillion (10<sup>12</sup>) liters, this bioleaching heap is arguably the world's largest industrial bioreactor.</p><p>Bioleaching of copper ores is a two-step process: first, the biological oxidation of Fe(II) to produce Fe(III); second, the chemical oxidation of Cu(I) to the more soluble Cu(II) by Fe(III) which is reduced to Fe(II) in the process. <i>A. ferrooxidans</i> plays a key role by reoxidizing the Fe(II) to Fe(III), thus completing the cycle and allowing bioleaching to continue (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-2164-9-597#Fig1">1</a>). The sulfuric acid produced by the biological oxidation of reduced sulfur compounds also promotes the solubilization of the Cu(II). Copper is recovered from this acidic solution using physico-chemical technologies such as solvent extraction and electroplating.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-1" data-title="Figure 1"><figure><figcaption><b id="Fig1" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 1</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.1186/1471-2164-9-597/figures/1" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig1_HTML.jpg?as=webp"><img aria-describedby="Fig1" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig1_HTML.jpg" alt="figure 1" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-1-desc"><p><b><i>A. ferrooxidans</i></b> <b>and its proposed role in bioleaching</b>. The chemolithoautotrophic metabolism of <i>A. ferrooxidans</i> results in the oxidation/reduction of iron and sulfur compounds and the solubilization of copper and other commercially valuable metals in a process called bioleaching or biomining. It also results in the production of acidified solutions in pristine environments and acid mine drainage in bioleaching operations. A) Model of copper bioleaching by <i>A. ferrooxidans</i>. B) Oxidation/reduction reactions carried out by <i>A. ferrooxidans</i>. The scheme provided here presents the basic concepts of bioleaching and further details are provided in the review [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Rawlings DE: Heavy metal mining using microbes. Annu Rev Microbiol. 2002, 56: 65-91. 10.1146/annurev.micro.56.012302.161052." href="/articles/10.1186/1471-2164-9-597#ref-CR4" id="ref-link-section-d25988610e636">4</a>]. C) Acid mine drainage in the Rio Tinto, Spain, derived from naturally occurring pyritic ore bodies and abandoned mine workings initiated in pre-Roman times [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Davis RA, Welty AT, Borrego J, Morales JA, Pendon JG, Ryan JG: Rio Tinto estuary (Spain): 5000 years of pollution. Environmental Geology. 2000, 39 (10): 1107-1116. 10.1007/s002549900096." href="/articles/10.1186/1471-2164-9-597#ref-CR3" id="ref-link-section-d25988610e640">3</a>]. D) Commercial bioleaching heap for copper recovery, Chile. 3PG: 3-phosphoglycerate.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.1186/1471-2164-9-597/figures/1" data-track-dest="link:Figure1 Full size image" aria-label="Full size image figure 1" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Bioleaching accounts for 10% of the copper production worldwide and is especially important as a technology for ores with a low percentage of copper that are otherwise uneconomical to extract. Another attractive feature of bioleaching is that it does not produce pollutants such as sulfur dioxide and arsenic that result from smelting. However, bioleaching does generate acid mine drainage that must be managed to prevent its release into the environment. The importance of bioleaching is likely to increase in the future as the mineral industry exploits ore deposits with lower copper content as richer ores become depleted. The increasing importance of bioleaching as a biotechnological process is stimulating increasing interest in the biology of <i>A. ferrooxidans</i> and associated bioleaching microorganisms.</p><p><i>A. ferrooxidans</i> is one of the few microorganisms known to gain energy by the oxidation of ferrous iron in acidic environments, using the low pH of its natural environment to generate reverse electron flow from Fe(II) to NADH [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Levican G, Bruscella P, Guacunano M, Inostroza C, Bonnefoy V, Holmes DS, Jedlicki E: Characterization of the petI and res operons of Acidithiobacillus ferrooxidans. J Bacteriol. 2002, 184 (5): 1498-1501." href="/articles/10.1186/1471-2164-9-597#ref-CR5" id="ref-link-section-d25988610e663">5</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Bruscella P, Appia-Ayme C, Levican G, Ratouchniak J, Jedlicki E, Holmes DS, Bonnefoy V: Differential expression of two bc1 complexes in the strict acidophilic chemolithoautotrophic bacterium Acidithiobacillus ferrooxidans suggests a model for their respective roles in iron or sulfur oxidation. Microbiology. 2007, 153 (Pt 1): 102-110. 10.1099/mic.0.2006/000067-0." href="/articles/10.1186/1471-2164-9-597#ref-CR8" id="ref-link-section-d25988610e666">8</a>]. It can also obtain energy by the oxidation of reduced sulfur compounds, hydrogen, and formate [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Drobner E, Huber H, Stetter KO: Thiobacillus ferrooxidans, a facultative hydrogen oxidizer. Appl Environ Microbiol. 1990, 56 (9): 2922-2923." href="/articles/10.1186/1471-2164-9-597#ref-CR9" id="ref-link-section-d25988610e669">9</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Pronk JT, Meijer WM, Hazeu W, van Dijken JP, Bos P, Kuenen JG: Growth of Thiobacillus ferrooxidans on Formic Acid. Appl Environ Microbiol. 1991, 57 (7): 2057-2062." href="/articles/10.1186/1471-2164-9-597#ref-CR10" id="ref-link-section-d25988610e672">10</a>]. The microorganism makes an important contribution to the biogeochemical cycling of metals in the environment and has the potential to assist in the remediation of metal contaminated sites by its ability to oxidize and reduce metals. Ferric iron and sulfuric acid are major by-products of its energy-transducing processes, and these chemicals can mobilize metals in the environment including toxic metals such as arsenic [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Duquesne K, Lebrun S, Casiot C, Bruneel O, Personne JC, Leblanc M, Elbaz-Poulichet F, Morin G, Bonnefoy V: Immobilization of arsenite and ferric iron by Acidithiobacillus ferrooxidans and its relevance to acid mine drainage. Appl Environ Microbiol. 2003, 69 (10): 6165-6173. 10.1128/AEM.69.10.6165-6173.2003." href="/articles/10.1186/1471-2164-9-597#ref-CR11" id="ref-link-section-d25988610e675">11</a>]. It can also reduce ferric ion and elemental sulfur, thus promoting the recycling of iron and sulfur compounds under anaerobic conditions [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Sugio T, Domatsu C, Munakata O, Tano T, Imai K: Role of a Ferric Ion-Reducing System in Sulfur Oxidation of Thiobacillus ferrooxidans. Appl Environ Microbiol. 1985, 49 (6): 1401-1406." href="/articles/10.1186/1471-2164-9-597#ref-CR12" id="ref-link-section-d25988610e679">12</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Ng KY, Sawada R, Inoue S, Kamimura K, Sugio T: Purification and some properties of sulfur reductase from the iron-oxidizing bacterium Thiobacillus ferrooxidans NASF-1. J Biosci Bioeng. 2000, 90 (2): 199-203. 10.1016/S1389-1723(00)80110-3." href="/articles/10.1186/1471-2164-9-597#ref-CR13" id="ref-link-section-d25988610e682">13</a>]. Since the microorganism can also fix CO<sub>2</sub> and nitrogen, it is thought to be a primary producer of carbon and nitrogen in acidic, nutrient-poor environments [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Heinhorst S, Baker SH, Johnson DR, Davies PS, Cannon GC, Shively JM: Two Copies of form I RuBisCO genes in Acidithiobacillus ferrooxidans ATCC 23270. Curr Microbiol. 2002, 45 (2): 115-117. 10.1007/s00284-001-0094-5." href="/articles/10.1186/1471-2164-9-597#ref-CR14" id="ref-link-section-d25988610e687">14</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Rowe OF, Sanchez-Espana J, Hallberg KB, Johnson DB: Microbial communities and geochemical dynamics in an extremely acidic, metal-rich stream at an abandoned sulfide mine (Huelva, Spain) underpinned by two functional primary production systems. Environ Microbiol. 2007, 9 (7): 1761-1771. 10.1111/j.1462-2920.2007.01294.x." href="/articles/10.1186/1471-2164-9-597#ref-CR17" id="ref-link-section-d25988610e690">17</a>].</p><p>The study of <i>A. ferrooxidans</i> offers exceptional opportunities to probe life in extremely acidic environments. It may also offer insights into ancient ways of life in Archaean, euxinic, acidic seas [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Dietrich LE, Tice MM, Newman DK: The co-evolution of life and Earth. Curr Biol. 2006, 16 (11): R395-400. 10.1016/j.cub.2006.05.017." href="/articles/10.1186/1471-2164-9-597#ref-CR18" id="ref-link-section-d25988610e699">18</a>] and suggest potential biomarkers to be used when searching for evidence of extra-terrestrial life [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Gonzalez-Toril E, Martinez-Frias J, Gomez Gomez JM, Rull F, Amils R: Iron meteorites can support the growth of acidophilic chemolithoautotrophic microorganisms. Astrobiology. 2005, 5 (3): 406-414. 10.1089/ast.2005.5.406." href="/articles/10.1186/1471-2164-9-597#ref-CR19" id="ref-link-section-d25988610e702">19</a>]. One of its unusual properties is its ability to aerobically oxidize solid substrates such as pyrite (FeS<sub>2</sub>). Since the substrate cannot enter the cell, initial electron removal must take place either within the outer cell membrane or completely outside the cell. Although a substantial body of information exists regarding the use of solid minerals as electron sinks for biological processes (e.g., the reduction of ferric iron [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Nealson KH, Saffarini D: Iron and manganese in anaerobic respiration: environmental significance, physiology, and regulation. Annu Rev Microbiol. 1994, 48: 311-343. 10.1146/annurev.mi.48.100194.001523." href="/articles/10.1186/1471-2164-9-597#ref-CR20" id="ref-link-section-d25988610e707">20</a>]), considerably less is known about how microorganisms recognize, attach to, and extract electrons from solid substrates. Investigations into the fundamental interactions between bacteria and mineral surfaces are critical for understanding the intricacies of interfacial biochemistry, biofilm formation, bacterial recognition of mineral surfaces, and the dispersal of microorganisms in the environment.</p><p><i>A. ferrooxidans</i> thrives in mineral rich, acid environments where the concentration of dissolved ferrous iron can be as high as 10<sup>-1</sup> M, about 10<sup>16</sup> times that found in circum-neutral environments. The abundance of soluble iron has the potential to pose severe oxidative stress that could lead to DNA and protein damage via the Fenton reaction. This prompts questions as to the mechanisms that <i>A. ferrooxidans</i> employs for iron assimilation and homeostasis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Quatrini R, Lefimil C, Holmes DS, Jedlicki E: The ferric iron uptake regulator (Fur) from the extreme acidophile Acidithiobacillus ferrooxidans. Microbiology. 2005, 151 (Pt 6): 2005-2015. 10.1099/mic.0.27581-0." href="/articles/10.1186/1471-2164-9-597#ref-CR21" id="ref-link-section-d25988610e722">21</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Quatrini R, Jedlicki E, Holmes DS: Genomic insights into the iron uptake mechanisms of the biomining microorganism Acidithiobacillus ferrooxidans. J Ind Microbiol Biotechnol. 2005, 32 (11–12): 606-614. 10.1007/s10295-005-0233-2." href="/articles/10.1186/1471-2164-9-597#ref-CR22" id="ref-link-section-d25988610e725">22</a>] and how it balances its use of iron as both a micronutrient and as a required energy source. In its natural environment, it must also confront unusually severe toxicity due to the high concentration of dissolved metals (e.g., copper, arsenic, mercury).</p><p>Although the internal pH of <i>A. ferrooxidans</i> is about pH 6.5, proteins that are either wholly or partially outside the inner membrane must function at pH 1–2, raising fundamental questions regarding how they fold and make protein-protein contact when confronted with such an extremely high proton concentration. It also raises questions as to how proton-driven membrane transport and energy processes function in the face of a proton motif force (pmf) across the inner membrane that is several orders of magnitude higher than typically found in neutrophilic environments.</p><p>Unfortunately, the lack of a well-developed system for genetic manipulation has prevented thorough exploration of the molecular biology and physiology of <i>A. ferrooxidans</i>. A bioinformatics-based analysis of its genome offers a powerful tool for investigating its metabolism. However, many of the earlier investigations of its genetics and metabolism were carried out on a variety of strains, some of which may be only distantly (or not at all) related to <i>A. ferrooxidans</i>. This allows the possibility that some experimental results, including enzyme identifications were not reliable indicators of the metabolism of the species. Genomic analysis of the type strain of <i>A. ferrooxidans</i> can provide a more coherent view of the gene content and metabolic potential of the species.</p><p>An analysis of amino acid metabolism based on the draft genome sequence of <i>A. ferrooxidans</i> ATCC 23270 was previously reported [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Selkov E, Overbeek R, Kogan Y, Chu L, Vonstein V, Holmes D, Silver S, Haselkorn R, Fonstein M: Functional analysis of gapped microbial genomes: amino acid metabolism of Thiobacillus ferrooxidans. Proc Natl Acad Sci USA. 2000, 97 (7): 3509-3514. 10.1073/pnas.97.7.3509." href="/articles/10.1186/1471-2164-9-597#ref-CR23" id="ref-link-section-d25988610e752">23</a>]. Here we present a complete, genome-based blueprint of the metabolic and regulatory capabilities of <i>A. ferrooxidans</i> and relate these findings to its unique lifestyle. This analysis will add to our understanding of the biochemical pathways that underpin the biogeochemical processes, metabolic functions, and evolution of microbial communities in acidic environments. This information also advances our understanding of the role of <i>A. ferrooxidans</i> in industrial bioleaching.</p></div></div></section><section data-title="Results and discussion"><div class="c-article-section" id="Sec2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec2">Results and discussion</h2><div class="c-article-section__content" id="Sec2-content"><h3 class="c-article__sub-heading" id="Sec3">1. Genomic properties</h3><p>The genome of <i>A. ferrooxidans</i> ATCC 23270 (type strain) consists of a single circular chromosome of 2,982,397 bp with a G+C content of 58.77%. No plasmids were detected in the type strain, although they occur in several other strains of [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Rawlings DE: The evolution of pTF-FC2 and pTC-F14, two related plasmids of the IncQ-family. Plasmid. 2005, 53 (2): 137-147. 10.1016/j.plasmid.2005.01.001." href="/articles/10.1186/1471-2164-9-597#ref-CR24" id="ref-link-section-d25988610e776">24</a>]. A total of 3217 protein-coding genes (CDSs) were predicted, of which 2070 (64.3%) were assigned a putative function (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/1471-2164-9-597#Tab1">1</a> and Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-2164-9-597#Fig2">2</a>). The genome encodes two ribosomal operons and 78 tRNA genes. A putative origin of replication (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-2164-9-597#Fig2">2</a>) has been identified from marginal GC skew variations in the genome and by the localization of the <i>dnaN</i> and <i>dnaA</i> genes (AFE0001 and AFE3309).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-2" data-title="Figure 2"><figure><figcaption><b id="Fig2" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 2</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.1186/1471-2164-9-597/figures/2" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig2_HTML.jpg?as=webp"><img aria-describedby="Fig2" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig2_HTML.jpg" alt="figure 2" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-2-desc"><p><b>Circular representation of the</b> <b><i>A. ferrooxidans</i></b> <b>ATCC 23270 genome sequence</b>. The two outer circles represent predicted protein encoding-genes on the forward and reverse strands, respectively. Functional categories are indicated by color, as follows: energy metabolism (green), DNA metabolism (red), protein synthesis (magenta), transcription (yellow), amino acid metabolism (orange), central intermediary metabolism (dark blue), cellular processes (light blue), nucleotide metabolism (turquoise), hypothetical and conserved hypothetical proteins (grey), mobile and extra-chromosomal elements (black), and general functions (brown). The third and fourth circles (forward and reverse strands) indicate major transposases and mobile elements (orange), plasmid-related genes (red), and phage elements (blue). The fifth and sixth circles (forward and reverse strands) indicate tRNA genes (gray). The seventh and eighth circles (forward and reverse strands) show genes predicted to be involved in sulfur (purple), iron (red), and hydrogen (orange) oxidation. The ninth and tenth circles show genomic GC bias and GC skew, respectively.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.1186/1471-2164-9-597/figures/2" data-track-dest="link:Figure2 Full size image" aria-label="Full size image figure 2" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-1"><figure><figcaption class="c-article-table__figcaption"><b id="Tab1" data-test="table-caption">Table 1 General features of the <i>A. ferrooxidans</i> ATCC 23270 genome.</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/10.1186/1471-2164-9-597/tables/1" aria-label="Full size table 1"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><h3 class="c-article__sub-heading" id="Sec4">2. Chemolithoautotrophy</h3><p><i>A. ferrooxidans</i> has a complete repertoire of genes required for a free-living, chemolithoautotrophic lifestyle, including those for CO<sub>2</sub> fixation and nucleotide and cofactor biosynthesis (Additional file <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/10.1186/1471-2164-9-597#MOESM1">1</a>). Analysis of an earlier draft genome had predicted genes for the pathways for synthesis of most amino acids, although ten genes were missing [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Selkov E, Overbeek R, Kogan Y, Chu L, Vonstein V, Holmes D, Silver S, Haselkorn R, Fonstein M: Functional analysis of gapped microbial genomes: amino acid metabolism of Thiobacillus ferrooxidans. Proc Natl Acad Sci USA. 2000, 97 (7): 3509-3514. 10.1073/pnas.97.7.3509." href="/articles/10.1186/1471-2164-9-597#ref-CR23" id="ref-link-section-d25988610e1158">23</a>]. Seven of these missing assignments have now been detected: a potential 6-phosphofructokinase in the glycolysis pathway (EC 2.7.1.11; AFE1807), pyruvate dehydrogenase (EC 1.2.4.1; AFE3068-70); shikimate kinase in the chorismate synthesis pathway and required for tryptophan, phenylalanine and tyrosine biosynthesis (EC 2.7.1.71; AFE0734); homeserine kinase in the threonine biosynthesis pathway (EC 2.7.1.39; AFE3097); N-acetyl-gamma-glutamil-1-phosphate reductase in the ornithine biosynthesis pathway and required for proline biosynthesis (EC 1.2.1.38; AFE3073); pirroline-5-carboxilate reductase involved in proline biosynthesis (EC 1.5.1.2; AFE0262); and asparagine synthase (EC 6.3.5.4: AFE1353). The three genes identified in <i>E. coli</i> which have not been found in <i>A. ferrooxidans</i> encode ornithine cyclodeaminase (EC 4.3.1.12) involved in proline biosynthesis, aromatic-amino-acid transaminase (EC 2.6.1.57), and arogenate dehydrogenase involved in tyrosine biosynthesis (EC 1.3.1.43).</p><p><i>A. ferrooxidans</i> has two glutamyl-tRNA synthetases: a more discriminating one (D-GluRS, AFE0422) that charges only Glu-tRNA(Glu) and a less discriminating one (ND-GluRS, AFE2222) that charges Glu-tRNA(Glu) and Glu-tRNA(Gln). The latter one is a required intermediate in protein synthesis in many organisms [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Nuñez H, Lefimil C, Min B, Soll D, Orellana O: In vivo formation of glutamyl-tRNA(Gln) in Escherichia coli by heterologous glutamyl-tRNA synthetases. FEBS Lett. 2004, 557 (1–3): 133-135. 10.1016/S0014-5793(03)01460-1." href="/articles/10.1186/1471-2164-9-597#ref-CR25" id="ref-link-section-d25988610e1172">25</a>]. An indirect regulation of glutamyl-tRNA synthetase by heme status suggests a potential metabolic connection between heme requirements, nitrogen, and central carbon metabolism [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Levican G, Katz A, de Armas M, Nunez H, Orellana O: Regulation of a glutamyl-tRNA synthetase by the heme status. Proc Natl Acad Sci USA. 2007, 104 (9): 3135-3140. 10.1073/pnas.0611611104." href="/articles/10.1186/1471-2164-9-597#ref-CR26" id="ref-link-section-d25988610e1175">26</a>].</p><p>Bioinformatic analysis supports prior experimental evidence that <i>A. ferrooxidans</i> has a versatile aerobic metabolism, capable of providing energy and reducing power requirements from inorganic compounds by the oxidation of Fe(II), reduced sulfur compounds, formate, and hydrogen. In addition, gene function predictions suggest that the microorganism is capable of anaerobic or micro-aerophilic growth using Fe(III) or elemental sulfur as alternative electron acceptors [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Ohmura N, Matsumoto N, Sasaki K, Saiki H: Electrochemical regeneration of Fe(III) to support growth on anaerobic iron respiration. Appl Environ Microbiol. 2002, 68 (1): 405-407. 10.1128/AEM.68.1.405-407.2002." href="/articles/10.1186/1471-2164-9-597#ref-CR27" id="ref-link-section-d25988610e1184">27</a>]. Many of the predictions were experimentally validated in a piece-meal fashion in a number of diverse strains of <i>A. ferrooxidans</i>, some of which may not belong to the same species [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Holmes D, Bonnefoy V: Insights into Iron and Sulfur Oxidation Mechanisms of Bioleaching Organisms. Biomining. Edited by: Rawlings DE, Johnson BD. 2006, Berlin: Springer-Verlag, 281-307." href="/articles/10.1186/1471-2164-9-597#ref-CR28" id="ref-link-section-d25988610e1190">28</a>]. Herein, we describe a coherent view of the metabolic potential of the type strain that will now allow a systematic appraisal of the diversity of the metabolic capacity of the <i>A. ferrooxidans</i> pangenome.</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec5">2.1 CO<sub>2</sub> fixation</h4><p><i>A. ferrooxidans</i> fixes CO<sub>2</sub> via the Calvin-Benson-Bassham reductive pentose phosphate cycle (Calvin cycle) using energy and reducing power derived from the oxidation of iron or sulfur [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Gale NL, Beck JV: Evidence for the Calvin cycle and hexose monophosphate pathway in Thiobacillus ferrooxidans. J Bacteriol. 1967, 94 (4): 1052-1059." href="/articles/10.1186/1471-2164-9-597#ref-CR29" id="ref-link-section-d25988610e1210">29</a>]. Early studies showed a relationship between the rate of iron and sulfur oxidation and the rate of CO<sub>2</sub> fixation in <i>A. ferrooxidans</i> (no strain designated) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Silver M: Oxidation of elemental sulfur and sulfur compounds and CO2 fixation by Ferrobacillus ferrooxidans (Thiobacillus ferrooxidans). Can J Microbiol. 1970, 16 (9): 845-849." href="/articles/10.1186/1471-2164-9-597#ref-CR30" id="ref-link-section-d25988610e1218">30</a>]. Several enzymes of the Calvin cycle have been described in <i>A. ferrooxidans</i>, including the key D-ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Gale NL, Beck JV: Evidence for the Calvin cycle and hexose monophosphate pathway in Thiobacillus ferrooxidans. J Bacteriol. 1967, 94 (4): 1052-1059." href="/articles/10.1186/1471-2164-9-597#ref-CR29" id="ref-link-section-d25988610e1225">29</a>]. Two structurally distinct forms of RuBisCO (I and II), with different catalytic properties, are typically present in autotrophs [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Tabita FR: Molecular and cellular regulation of autotrophic carbon dioxide fixation in microorganisms. Microbiol Rev. 1988, 52 (2): 155-189." href="/articles/10.1186/1471-2164-9-597#ref-CR31" id="ref-link-section-d25988610e1228">31</a>]. Genes encoding Form I (AFE3051-2) have been cloned and characterized from <i>A. ferrooxidans</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Pulgar V, Gaete L, Allende J, Orellana O, Jordana X, Jedlicki E: Isolation and nucleotide sequence of the Thiobacillus ferrooxidans genes for the small and large subunits of ribulose 1,5-bisphosphate carboxylase/oxygenase. FEBS Lett. 1991, 292 (1–2): 85-89. 10.1016/0014-5793(91)80840-Y." href="/articles/10.1186/1471-2164-9-597#ref-CR32" id="ref-link-section-d25988610e1234">32</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Kusano T, Takeshima T, Inoue C, Sugawara K: Evidence for two sets of structural genes coding for ribulose bisphosphate carboxylase in Thiobacillus ferrooxidans. J Bacteriol. 1991, 173 (22): 7313-7323." href="/articles/10.1186/1471-2164-9-597#ref-CR33" id="ref-link-section-d25988610e1237">33</a>]. Gene clusters potentially encoding a second copy of Form I (AFE1690-1) and a copy of Form II (AFE2155) were predicted and shown to be differentially expressed depending on whether <i>A. ferrooxidans</i> was grown on iron- or sulfur-containing medium. [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Quatrini R, Appia-Ayme C, Denis C, Ratouchniak J, Veloso F, Valdes J, Lefimil C, Silver S, Roberto F, Orellana O: Insights into the Iron and Sulfur Energetic Metabolism of Acidthiobacillus ferrooxidans by Microarray Transcriptome Profiling. Hydrometallurgy. 2006, 83: 263-272. 10.1016/j.hydromet.2006.03.030." href="/articles/10.1186/1471-2164-9-597#ref-CR34" id="ref-link-section-d25988610e1244">34</a>]. A gene predicted to encode a novel Rubisco-like protein known as Form IV [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Imker HJ, Fedorov AA, Fedorov EV, Almo SC, Gerlt JA: Mechanistic diversity in the RuBisCO superfamily: the "enolase" in the methionine salvage pathway in Geobacillus kaustophilus. Biochemistry. 2007, 46 (13): 4077-4089. 10.1021/bi7000483." href="/articles/10.1186/1471-2164-9-597#ref-CR35" id="ref-link-section-d25988610e1247">35</a>] was recently identified in the genome (AFE0435) and is suggested to be involved in stress response (Esparza-Mantilla, personal communication) (Additional file).</p><p>The genomic organization of the three gene clusters encoding the Rubisco type I and II enzymes in <i>A. ferrooxidans</i> is similar to that found in <i>Hydrogenovibrio marinus</i> strain MH-110, an obligate chemolithoautotrophic, hydrogen-oxidizing, marine bacterium. In <i>H. marinus</i>, these three-gene clusters are regulated in response to CO<sub>2</sub> concentration, suggesting the ability to adapt to environmental conditions with different levels of CO<sub>2</sub> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Yoshizawa Y, Toyoda K, Arai H, Ishii M, Igarashi Y: CO2-responsive expression and gene organization of three ribulose-1,5-bisphosphate carboxylase/oxygenase enzymes and carboxysomes in Hydrogenovibrio marinus strain MH-110. J Bacteriol. 2004, 186 (17): 5685-5691. 10.1128/JB.186.17.5685-5691.2004." href="/articles/10.1186/1471-2164-9-597#ref-CR36" id="ref-link-section-d25988610e1267">36</a>].</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec6">2.2 Energy metabolism</h4><h5 class="c-article__sub-heading c-article__sub-heading--small" id="Sec7">2.2.1 Aerobic Iron oxidation</h5><p>Since ferrous iron [Fe(II)] is rapidly oxidized by atmospheric oxygen at neutral pH, iron exists primarily in the oxidized form [Fe(III)] in aerobic environments. Therefore, ferrous iron is available for microbial oxidation principally in acidic environments where chemical oxidation is slow and Fe(II) is soluble, in anoxic conditions such as in marine sediments and at the interface between aerobic and anaerobic atmospheres [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Straub KL, Rainey FA, Widdel F: Rhodovulum iodosum sp. nov. and Rhodovulum robiginosum sp. nov., two new marine phototrophic ferrous-iron-oxidizing purple bacteria. Int J Syst Bacteriol. 1999, 49 (Pt 2): 729-735." href="/articles/10.1186/1471-2164-9-597#ref-CR37" id="ref-link-section-d25988610e1283">37</a>]. In anoxic conditions, phototrophic bacteria can use light energy to couple the oxidation of Fe(II) to reductive CO<sub>2</sub> fixation. Although little is known about the mechanisms involved, this process has been postulated to be an ancient form of metabolism and to represent a transition step in the evolution of oxygenic photosynthesis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Jiao Y, Newman DK: The pio operon is essential for phototrophic Fe(II) oxidation in Rhodopseudomonas palustris TIE-1. J Bacteriol. 2007, 189 (5): 1765-1773. 10.1128/JB.00776-06." href="/articles/10.1186/1471-2164-9-597#ref-CR38" id="ref-link-section-d25988610e1288">38</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Croal LR, Jiao Y, Newman DK: The fox operon from Rhodobacter strain SW2 promotes phototrophic Fe(II) oxidation in Rhodobacter capsulatus SB1003. J Bacteriol. 2007, 189 (5): 1774-1782. 10.1128/JB.01395-06." href="/articles/10.1186/1471-2164-9-597#ref-CR39" id="ref-link-section-d25988610e1291">39</a>].</p><p>The bioinformatics analysis of the genome sequence of <i>A. ferrooxidans</i> has permitted the identification of the main components of the electron transport chain involved in iron and sulfur oxidation (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-2164-9-597#Fig3">3</a>). Genes encoding iron oxidation functions are organized in two transcriptional units, the <i>petI</i> and <i>rus</i> operons. The <i>petI</i> operon (<i>petC-1, petB-1, petA-1, sdrA-1</i>, and <i>cycA-1;</i> AFE3107-11) encode the three subunits of the <i>bc</i><sub>1</sub> complex (PetCAB), a predicted short chain dehydrogenase (Sdr) of unknown function, and a cytochrome <i>c</i><sub>4</sub> that has been suggested to receive electrons from rusticyanin and pass them to the <i>bc</i><sub>1</sub> complex [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Levican G, Bruscella P, Guacunano M, Inostroza C, Bonnefoy V, Holmes DS, Jedlicki E: Characterization of the petI and res operons of Acidithiobacillus ferrooxidans. J Bacteriol. 2002, 184 (5): 1498-1501." href="/articles/10.1186/1471-2164-9-597#ref-CR5" id="ref-link-section-d25988610e1332">5</a>]. The <i>petI</i> operon has been analyzed experimentally in <i>A. ferrooxidans</i> strain ATCC 19859 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Levican G, Bruscella P, Guacunano M, Inostroza C, Bonnefoy V, Holmes DS, Jedlicki E: Characterization of the petI and res operons of Acidithiobacillus ferrooxidans. J Bacteriol. 2002, 184 (5): 1498-1501." href="/articles/10.1186/1471-2164-9-597#ref-CR5" id="ref-link-section-d25988610e1341">5</a>] and recently in strain ATCC33020 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Bruscella P, Appia-Ayme C, Levican G, Ratouchniak J, Jedlicki E, Holmes DS, Bonnefoy V: Differential expression of two bc1 complexes in the strict acidophilic chemolithoautotrophic bacterium Acidithiobacillus ferrooxidans suggests a model for their respective roles in iron or sulfur oxidation. Microbiology. 2007, 153 (Pt 1): 102-110. 10.1099/mic.0.2006/000067-0." href="/articles/10.1186/1471-2164-9-597#ref-CR8" id="ref-link-section-d25988610e1344">8</a>].</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-3" data-title="Figure 3"><figure><figcaption><b id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 3</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.1186/1471-2164-9-597/figures/3" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig3_HTML.jpg?as=webp"><img aria-describedby="Fig3" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig3_HTML.jpg" alt="figure 3" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-3-desc"><p><b>Genome-based models for the oxidation of ferrous iron and reduced inorganic sulfur compounds (RISCs)</b>. Schematic representation of enzymes and electron transfer proteins involved in the oxidation of (A) ferrous iron and (B) reduced inorganic sulfur compounds (RISCs). Proteins and protein complexes are described in the text.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.1186/1471-2164-9-597/figures/3" data-track-dest="link:Figure3 Full size image" aria-label="Full size image figure 3" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>The <i>rus</i> operon (<i>cyc2, cyc1, hyp, coxB, coxA coxC, coxD</i>, and <i>rus</i>; AFE3146-53) encodes two c-type cytochromes (Cyc1 and Cyc2), components of the aa3-type cytochrome oxidase (CoxBACD), and rusticyanin, respectively [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Appia-Ayme C, Guiliani N, Ratouchniak J, Bonnefoy V: Characterization of an operon encoding two c-type cytochromes, an aa(3)-type cytochrome oxidase, and rusticyanin in Thiobacillus ferrooxidans ATCC 33020. Appl Environ Microbiol. 1999, 65 (11): 4781-4787." href="/articles/10.1186/1471-2164-9-597#ref-CR40" id="ref-link-section-d25988610e1380">40</a>]. Cyc2 has been shown to accept electrons directly from Fe(II) and, given its location in the outer membrane, may carry out the first step in Fe(II) oxidation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Yarzabal A, Brasseur G, Ratouchniak J, Lund K, Lemesle-Meunier D, DeMoss JA, Bonnefoy V: The high-molecular-weight cytochrome c Cyc2 of Acidithiobacillus ferrooxidans is an outer membrane protein. J Bacteriol. 2002, 184 (1): 313-317. 10.1128/JB.184.1.313-317.2002." href="/articles/10.1186/1471-2164-9-597#ref-CR41" id="ref-link-section-d25988610e1383">41</a>]. These proteins are thought to form a "respiratory supercomplex" that spans the outer and the inner membranes and transfers electrons from iron (or pyrite) to oxygen [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Appia-Ayme C, Guiliani N, Ratouchniak J, Bonnefoy V: Characterization of an operon encoding two c-type cytochromes, an aa(3)-type cytochrome oxidase, and rusticyanin in Thiobacillus ferrooxidans ATCC 33020. Appl Environ Microbiol. 1999, 65 (11): 4781-4787." href="/articles/10.1186/1471-2164-9-597#ref-CR40" id="ref-link-section-d25988610e1387">40</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="Castelle C, Guiral M, Malarte G, Ledgham F, Leroy G, Brugna M, Giudici-Orticoni MT: A new Fe-oxidizing/O2-reducing supercomplex spanning both inner and outer membranes, isolated from the extreme acidophile Acidithiobacillus ferrooxidans. J Biol Chem." href="/articles/10.1186/1471-2164-9-597#ref-CR42" id="ref-link-section-d25988610e1390">42</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 43" title="Fukumori F, Yano T, Sato A, Yamanaka T: Fe(II)-oxidizing enzyme purified from Thiobacillus ferrooxidans. FEMS Microbiology Letters. 1988, 50 (2–3): 169-172. 10.1111/j.1574-6968.1988.tb02932.x." href="/articles/10.1186/1471-2164-9-597#ref-CR43" id="ref-link-section-d25988610e1393">43</a>]. Based on transcriptional, biochemical, and genetic studies [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Holmes D, Bonnefoy V: Insights into Iron and Sulfur Oxidation Mechanisms of Bioleaching Organisms. Biomining. Edited by: Rawlings DE, Johnson BD. 2006, Berlin: Springer-Verlag, 281-307." href="/articles/10.1186/1471-2164-9-597#ref-CR28" id="ref-link-section-d25988610e1396">28</a>], it was proposed that electrons from ferrous iron oxidation flow through Cyc2 to rusticyanin. From there, some of the electrons feed the "downhill electron pathway" through <i>c</i>-cytochrome Cyc1 to <i>aa</i><sub>3</sub> cytochrome oxidase, some the "uphill electron pathway" that regenerates the universal electron donor NADH by the reverse electron flow through <i>c</i>-cytochrome CycA1--> <i>bc</i><sub>1</sub> complex-->ubiquinone pool-->NADH dehydrogenase (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-2164-9-597#Fig3">3a</a>).</p><p>Genome analysis suggests a solution to a long-standing controversy. A HiPIP (high potential iron-sulfur protein) encoded by <i>iro</i> has been postulated to be the first electron acceptor from Fe(II) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Cavazza C, Guigliarelli B, Bertrand P, Bruschi M: Biochemical and EPR characterization of a high potential iron-sulfur protein in Thiobacillus ferrooxidans. FEMS Microbiology Letters. 1995, 130 (2–3): 193-199. 10.1111/j.1574-6968.1995.tb07719.x." href="/articles/10.1186/1471-2164-9-597#ref-CR44" id="ref-link-section-d25988610e1423">44</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 45" title="Bruscella P, Cassagnaud L, Ratouchniak J, Brasseur G, Lojou E, Amils R, Bonnefoy V: The HiPIP from the acidophilic Acidithiobacillus ferrooxidans is correctly processed and translocated in Escherichia coli, in spite of the periplasm pH difference between these two micro-organisms. Microbiology. 2005, 151 (Pt 5): 1421-1431. 10.1099/mic.0.27476-0." href="/articles/10.1186/1471-2164-9-597#ref-CR45" id="ref-link-section-d25988610e1426">45</a>]. However, transcriptional studies of <i>iro</i> in <i>A. ferrooxidans</i> ATCC33020 suggested that it may be involved in sulfur oxidation. In our analysis of the type strain, <i>iro</i> (AFE2732) was found to be associated with the petII gene cluster thought to be involved in sulfur oxidation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 46" title="Quatrini R, Appia-Ayme C, Denis Y, Ratouchniak J, Veloso F, Valdes J, Lefimil C, Silver S, Roberto F, Orellana O: Global analysis of the ferrous iron and sulfur energetic metabolism of Acidithiobacillus ferrooxidans by microarray transcriptome profiling. 16th International Biohydrometallurgy Symposium: 2005. 2005, Cape Town, South Africa: elsevier, 761-771." href="/articles/10.1186/1471-2164-9-597#ref-CR46" id="ref-link-section-d25988610e1439">46</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 47" title="Kusano T, Takeshima T, Sugawara K, Inoue C, Shiratori T, Yano T, Fukumori Y, Yamanaka T: Molecular cloning of the gene encoding Thiobacillus ferrooxidans Fe(II) oxidase. High homology of the gene product with HiPIP. J Biol Chem. 1992, 267 (16): 11242-11247." href="/articles/10.1186/1471-2164-9-597#ref-CR47" id="ref-link-section-d25988610e1442">47</a>], thus making it unlikely that Iro is the key iron-oxidizing enzyme.</p><h5 class="c-article__sub-heading c-article__sub-heading--small" id="Sec8">2.2.2 Aerobic oxidation of reduced inorganic sulfur compounds (RISCs)</h5><p>Genes encoding enzymes and electron transfer proteins predicted to be involved in the oxidation of reduced inorganic sulfur compounds (RISCs) were detected in the genome (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-2164-9-597#Fig3">3b</a>). The oxidative and electron transfer pathways for RISCs are more complicated than those for Fe(II) oxidation, making their prediction and elucidation more difficult [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 48" title="Pronk JT, Meulemberg R, Hazeu W, Bos P, Kuenen JG: Oxidation of reduced inorganic sulphur compounds by acidophilic thiobacilli. FEMS Microbiology letters. 1990, 75 (2–3): 293-306. 10.1111/j.1574-6968.1990.tb04103.x." href="/articles/10.1186/1471-2164-9-597#ref-CR48" id="ref-link-section-d25988610e1456">48</a>]. To add further complication, some steps occur spontaneously, without enzymatic catalysis. Previous experimental studies in various strains of <i>A. ferrooxidans</i> detected several enzymatic activities involved in the oxidation of RISCs [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Rohwerder T, Gehrke T, Kinzler K, Sand W: Bioleaching review part A: progress in bioleaching: fundamentals and mechanisms of bacterial metal sulfide oxidation. Appl Microbiol Biotechnol. 2003, 63 (3): 239-248. 10.1007/s00253-003-1448-7." href="/articles/10.1186/1471-2164-9-597#ref-CR1" id="ref-link-section-d25988610e1462">1</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Holmes D, Bonnefoy V: Insights into Iron and Sulfur Oxidation Mechanisms of Bioleaching Organisms. Biomining. Edited by: Rawlings DE, Johnson BD. 2006, Berlin: Springer-Verlag, 281-307." href="/articles/10.1186/1471-2164-9-597#ref-CR28" id="ref-link-section-d25988610e1465">28</a>], but some of these activities had not been linked to specific genes. Based on genome analysis, some of these missing assignments are predicted and also some novel genes involved in the oxidation of thiosulfate, sulfide, and tetrathionate are suggested.</p><p>Experimentally validated components of RISC metabolism include: the <i>pet-II</i> operon (AFE2727-31) and alternative quinol oxidases of the <i>bd</i> (AFE0954-5) and <i>bo</i><sub>3</sub> families (AFE0631-4) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Brasseur G, Levican G, Bonnefoy V, Holmes D, Jedlicki E, Lemesle-Meunier D: Apparent redundancy of electron transfer pathways via bc(1) complexes and terminal oxidases in the extremophilic chemolithoautotrophic Acidithiobacillus ferrooxidans. Biochim Biophys Acta. 2004, 1656 (2–3): 114-126." href="/articles/10.1186/1471-2164-9-597#ref-CR7" id="ref-link-section-d25988610e1481">7</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Bruscella P, Appia-Ayme C, Levican G, Ratouchniak J, Jedlicki E, Holmes DS, Bonnefoy V: Differential expression of two bc1 complexes in the strict acidophilic chemolithoautotrophic bacterium Acidithiobacillus ferrooxidans suggests a model for their respective roles in iron or sulfur oxidation. Microbiology. 2007, 153 (Pt 1): 102-110. 10.1099/mic.0.2006/000067-0." href="/articles/10.1186/1471-2164-9-597#ref-CR8" id="ref-link-section-d25988610e1484">8</a>]; a sulfide/quinone oxidoreductase encoded by <i>sqr</i> (AFE0267) suggested to be involved in the oxidation of sulfide to sulfur [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 49" title="Wakai S, Kikumoto M, Kanao T, Kamimura K: Involvement of sulfide:quinone oxidoreductase in sulfur oxidation of an acidophilic iron-oxidizing bacterium, Acidithiobacillus ferrooxidans NASF-1. Biosci Biotechnol Biochem. 2004, 68 (12): 2519-2528. 10.1271/bbb.68.2519." href="/articles/10.1186/1471-2164-9-597#ref-CR49" id="ref-link-section-d25988610e1491">49</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 50" title="Wakai S, Tsujita M, Kikumoto M, Manchur MA, Kanao T, Kamimura K: Purification and characterization of sulfide:quinone oxidoreductase from an acidophilic iron-oxidizing bacterium, Acidithiobacillus ferrooxidans. Biosci Biotechnol Biochem. 2007, 71 (11): 2735-2742. 10.1271/bbb.70332." href="/articles/10.1186/1471-2164-9-597#ref-CR50" id="ref-link-section-d25988610e1494">50</a>]; and a tetrathionate hydrolase encoded by <i>tetH</i> (AFE0029) thought to be involved in the oxidation of tetrathionate [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 51" title="Kanao T, Kamimura K, Sugio T: Identification of a gene encoding a tetrathionate hydrolase in Acidithiobacillus ferrooxidans. J Biotechnol. 2007, 132 (1): 16-22. 10.1016/j.jbiotec.2007.08.030." href="/articles/10.1186/1471-2164-9-597#ref-CR51" id="ref-link-section-d25988610e1500">51</a>].</p><p>The two homologs of <i>doxDA</i> (AFE0044; AFE0048) present in the genome are predicted to encode a thiosulfate/quinone oxidoreductase. Both appear to be a fusion of the separate <i>doxD</i> and <i>doxA</i> genes that are found in other organisms such as <i>A. ambivalens</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 52" title="Purschke WG, Schmidt CL, Petersen A, Schafer G: The terminal quinol oxidase of the hyperthermophilic archaeon Acidianus ambivalens exhibits a novel subunit structure and gene organization. J Bacteriol. 1997, 179 (4): 1344-1353." href="/articles/10.1186/1471-2164-9-597#ref-CR52" id="ref-link-section-d25988610e1518">52</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 53" title="Muller FH, Bandeiras TM, Urich T, Teixeira M, Gomes CM, Kletzin A: Coupling of the pathway of sulphur oxidation to dioxygen reduction: characterization of a novel membrane-bound thiosulphate:quinone oxidoreductase. Mol Microbiol. 2004, 53 (4): 1147-1160. 10.1111/j.1365-2958.2004.04193.x." href="/articles/10.1186/1471-2164-9-597#ref-CR53" id="ref-link-section-d25988610e1522">53</a>]. Both are located in a major gene cluster composed of two divergent gene clusters. The first region (AFE0050-47) encodes a protein with TAT-signal peptide (IPR006311, TIGR01409), a periplasmic solute-binding protein, the first <i>doxDA</i> gene, and a conserved hypothetical protein. The second region (AFE0046-42) encodes a conserved hypothetical protein, a rhodanese enzyme that splits thiosulfate into sulfur and sulfite [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Tabita R, Silver M, Lundgren DG: The rhodanese enzyme of Ferrobacillus ferrooxidans (Thiobacillus ferrooxidans). Can J Biochem. 1969, 47 (12): 1141-1145." href="/articles/10.1186/1471-2164-9-597#ref-CR54" id="ref-link-section-d25988610e1528">54</a>], the second copy of <i>doxDA</i>, a periplasmic solute-binding protein, a second copy of a gene encoding a protein with TAT-signal peptide (IPR006311, TIGR01409), and a gene encoding a putative carboxylate transporter. We have detected a similar organization in the <i>Gluconobacter oxydans</i> genome.</p><p>Five genes, predicted to encode thiosulfate sulfur transferase (rhodanese) proteins (AFE2558, AFE2364, AFE1502, AFE0529 and AFE0151) are dispersed in the genome [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 55" title="Acosta M, Beard S, Ponce J, Vera M, Mobarec JC, Jerez CA: Identification of putative sulfurtransferase genes in the extremophilic Acidithiobacillus ferrooxidans ATCC 23270 genome: structural and functional characterization of the proteins. Omics. 2005, 9 (1): 13-29. 10.1089/omi.2005.9.13." href="/articles/10.1186/1471-2164-9-597#ref-CR55" id="ref-link-section-d25988610e1540">55</a>] but their roles in sulfur oxidation remain to be firmly established. Notably, some of these predictions are based on the presence of the rhodanese PFAM00581 motif associated with phosphatases and ubiquitin C-terminal hydrolases, in addition to sulfur oxidation. Genes were not detected for several enzymatic functions that have been experimentally demonstrated in other strains of <i>A. ferrooxidans</i> including the sulfur dioxygenase that oxidizes persulfide-sulfur to sulfite in <i>A. ferrooxidans</i> strain R1 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Rohwerder T, Gehrke T, Kinzler K, Sand W: Bioleaching review part A: progress in bioleaching: fundamentals and mechanisms of bacterial metal sulfide oxidation. Appl Microbiol Biotechnol. 2003, 63 (3): 239-248. 10.1007/s00253-003-1448-7." href="/articles/10.1186/1471-2164-9-597#ref-CR1" id="ref-link-section-d25988610e1549">1</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 56" title="Silver M, Lundgren DG: sulfur-oxidizing enzyme of Ferrobacillus ferrooxidans (Thiobacillus ferrooxidans). Can J Biochem. 1968, 46: 457-461. 10.1139/v68-309." href="/articles/10.1186/1471-2164-9-597#ref-CR56" id="ref-link-section-d25988610e1552">56</a>] and the sulfite oxidase that oxidizes sulfite to sulfate in <i>Ferrobacillus ferrooxidans</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Rohwerder T, Gehrke T, Kinzler K, Sand W: Bioleaching review part A: progress in bioleaching: fundamentals and mechanisms of bacterial metal sulfide oxidation. Appl Microbiol Biotechnol. 2003, 63 (3): 239-248. 10.1007/s00253-003-1448-7." href="/articles/10.1186/1471-2164-9-597#ref-CR1" id="ref-link-section-d25988610e1559">1</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 57" title="Vestal JR, Lundgren DG: The sulfite oxidase of Thiobacillus ferrooxidans (Ferrobacillus ferrooxidans). Can J Biochem. 1971, 49 (10): 1125-1130." href="/articles/10.1186/1471-2164-9-597#ref-CR57" id="ref-link-section-d25988610e1562">57</a>].</p><h5 class="c-article__sub-heading c-article__sub-heading--small" id="Sec9">2.2.3 Hydrogen and formate utilization</h5><p>Hydrogen utilization has been demonstrated experimentally in <i>A. ferrooxidans</i> ATCC 23270 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Drobner E, Huber H, Stetter KO: Thiobacillus ferrooxidans, a facultative hydrogen oxidizer. Appl Environ Microbiol. 1990, 56 (9): 2922-2923." href="/articles/10.1186/1471-2164-9-597#ref-CR9" id="ref-link-section-d25988610e1576">9</a>] and a group 2 hydrogenase from <i>A. ferrooxidans</i> ATCC 19859 has been characterized [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 58" title="Fischer J, Quentmeier A, Kostka S, Kraft R, Friedrich CG: Purification and characterization of the hydrogenase from Thiobacillus ferrooxidans. Arch Microbiol. 1996, 165 (5): 289-296. 10.1007/s002030050329." href="/articles/10.1186/1471-2164-9-597#ref-CR58" id="ref-link-section-d25988610e1582">58</a>], but there were no previous reports describing the hydrogenase genes and their genetic organization or their potential diversity. The <i>A. ferrooxidans</i> genome encodes four different types of hydrogenases based on the 2001 classification by Vignais et al. [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 59" title="Vignais PM, Billoud B, Meyer J: Classification and phylogeny of hydrogenases. FEMS Microbiol Rev. 2001, 25 (4): 455-501." href="/articles/10.1186/1471-2164-9-597#ref-CR59" id="ref-link-section-d25988610e1589">59</a>] (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-2164-9-597#Fig4">4</a>, Additional file <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/10.1186/1471-2164-9-597#MOESM3">3</a>). Group 1 [NiFe]-hydrogenases are membrane-bound respiratory enzymes that enable the cell to use molecular hydrogen as an energy source. <i>A. ferrooxidans</i> has both the predicted structural (AFE3283-86) and the maturation-related genes (AFE3281-2; AFE3287-90) required for production of a functional respiratory hydrogenase of this type. In addition, the small subunit of this predicted complex has the characteristic TAT-signal peptide used to target the full heterodimer to the periplasmic space [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 60" title="Sargent F, Berks BC, Palmer T: Assembly of membrane-bound respiratory complexes by the Tat protein-transport system. Arch Microbiol. 2002, 178 (2): 77-84. 10.1007/s00203-002-0434-2." href="/articles/10.1186/1471-2164-9-597#ref-CR60" id="ref-link-section-d25988610e1601">60</a>]. The genomic arrangement of the structural genes (<i>hynS-isp1-isp2-hynL</i>) is identical to that found in a thermoacidophilic archaeon (<i>Acidianus ambivalens</i>), a hyperthermophilic bacterium (<i>Aquifex aeolicus</i>), a denitrifying bacterium (<i>Thiobacillus denitrificans</i>), and two phototrophic sulfur bacteria (<i>Thiocapsa roseopersicina</i> and <i>Allochromatium vinosum</i>). Like <i>A. ferrooxidans</i>, all of these bacteria are chemoautotrophs that live in extreme environments, use inorganic energy sources, and have an active sulfur metabolism that oxidizes and reduces inorganic sulfur compounds [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 61" title="Friedrich CG, Bardischewsky F, Rother D, Quentmeier A, Fischer J: Prokaryotic sulfur oxidation. Curr Opin Microbiol. 2005, 8 (3): 253-259. 10.1016/j.mib.2005.04.005." href="/articles/10.1186/1471-2164-9-597#ref-CR61" id="ref-link-section-d25988610e1627">61</a>].</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-4" data-title="Figure 4"><figure><figcaption><b id="Fig4" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 4</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.1186/1471-2164-9-597/figures/4" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig4_HTML.jpg?as=webp"><img aria-describedby="Fig4" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig4_HTML.jpg" alt="figure 4" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-4-desc"><p><b>Diversity and genomic organization of predicted hydrogenases</b>. A) Schematic representation of the four predicted types of hydrogenase. B) Organization of the predicted operons encoding the four types of hydrogenase. C) Schematic representation of similarity between the group 4 hydrogenase genes in <i>M. barkeri</i> with the <i>A. ferrooxidans</i> group 4 hydrogenase (above) and NADH dehydrogenase subunits (below).</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.1186/1471-2164-9-597/figures/4" data-track-dest="link:Figure4 Full size image" aria-label="Full size image figure 4" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p><i>A. ferrooxidans</i> also encodes a group 2 cytoplasmic uptake [NiFe]-hydrogenase (AFE0701-2). Group 2 hydrogenases are induced during nitrogen fixation to utilize the molecular hydrogen generated [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 62" title="Appel J, Phunpruch S, Steinmuller K, Schulz R: The bidirectional hydrogenase of Synechocystis sp. PCC 6803 works as an electron valve during photosynthesis. Arch Microbiol. 2000, 173 (5–6): 333-338. 10.1007/s002030000139." href="/articles/10.1186/1471-2164-9-597#ref-CR62" id="ref-link-section-d25988610e1661">62</a>]. The cyanobacterial-like hydrogenase in <i>A. ferrooxidans</i> exhibits the characteristic features of uptake hydrogenases as determined by EPR and FTIR [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 63" title="Schroder O, Bleijlevens B, de Jongh TE, Chen Z, Li T, Fischer J, Forster J, Friedrich CG, Bagley KA, Albracht SP: Characterization of a cyanobacterial-like uptake [NiFe] hydrogenase: EPR and FTIR spectroscopic studies of the enzyme from Acidithiobacillus ferrooxidans. J Biol Inorg Chem. 2007, 12 (2): 212-233. 10.1007/s00775-006-0185-7." href="/articles/10.1186/1471-2164-9-597#ref-CR63" id="ref-link-section-d25988610e1667">63</a>]. Divergently oriented from the group 2 hydrogenase gene cluster is a predicted σ<sub>54</sub>-dependent hydrogenase transcriptional regulator (<i>hupR</i>) (AFE0700). HupR together with a histidine kinase forms part of a two-component regulatory system in <i>R. eutropha</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 64" title="Schwartz E, Buhrke T, Gerischer U, Friedrich B: Positive transcriptional feedback controls hydrogenase expression in Alcaligenes eutrophus H16. J Bacteriol. 1999, 181 (18): 5684-5692." href="/articles/10.1186/1471-2164-9-597#ref-CR64" id="ref-link-section-d25988610e1679">64</a>], but the histidine kinase appears to be absent from the <i>A. ferrooxidans</i> genome. Despite that, HupR is able to activate transcription in the non-phosphorylated form [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 65" title="Dischert W, Vignais PM, Colbeau A: The synthesis of Rhodobacter capsulatus HupSL hydrogenase is regulated by the two-component HupT/HupR system. Mol Microbiol. 1999, 34 (5): 995-1006. 10.1046/j.1365-2958.1999.01660.x." href="/articles/10.1186/1471-2164-9-597#ref-CR65" id="ref-link-section-d25988610e1685">65</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 67" title="van Soom C, Lerouge I, Vanderleyden J, Ruiz-Argueso T, Palacios JM: Identification and characterization of hupT, a gene involved in negative regulation of hydrogen oxidation in Bradyrhizobium japonicum. J Bacteriol. 1999, 181 (16): 5085-5089." href="/articles/10.1186/1471-2164-9-597#ref-CR67" id="ref-link-section-d25988610e1688">67</a>], indicating that HupR is still able to regulate transcription of the group 2 hydrogenase system in <i>A. ferrooxidans</i>.</p><p>Adjacent to the group 2 hydrogenase gene cluster and transcribed in the same direction is a predicted cysteine regulon transcriptional activator <i>cysB</i> (AFE0699). This is followed by a cluster of genes potentially involved in fermentation, including a predicted σ<sub>54</sub>-dependent transcriptional regulator and a group of <i>isc</i>-like genes (AFE0672-78). The latter gene group is thought to be involved in assembling the iron-sulfur cluster of the nitrogenase used in nitrogen fixation, thus suggesting a connection between hydrogen production by the group 2 hydrogenase and nitrogen fixation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 68" title="Valdes J, Veloso F, Jedlicki E, Holmes D: Metabolic reconstruction of sulfur assimilation in the extremophile Acidithiobacillus ferrooxidans based on genome analysis. BMC Genomics. 2003, 4 (1): 51-10.1186/1471-2164-4-51." href="/articles/10.1186/1471-2164-9-597#ref-CR68" id="ref-link-section-d25988610e1705">68</a>]. The close proximity of the fermentation gene cluster suggests an additional metabolic coupling with fermentative metabolism, perhaps as part of a σ<sub>54</sub> regulatory cascade operating in anaerobic or microaerophilic conditions.</p><p>The third predicted hydrogenase encodes a sulfhydrogenase, a group 3b cytoplasmic, bidirectional, heterotetrameric hydrogenase. This hydrogenase, in association with other proteins, binds soluble cofactors such as NAD, cofactor 420, and NADP [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 59" title="Vignais PM, Billoud B, Meyer J: Classification and phylogeny of hydrogenases. FEMS Microbiol Rev. 2001, 25 (4): 455-501." href="/articles/10.1186/1471-2164-9-597#ref-CR59" id="ref-link-section-d25988610e1713">59</a>]. Domain analysis predicts an F420 binding site in the α subunit (large hydrogenase subunit; AFE0937) and NAD- and FAD-binding sites in the γ subunit (AFE0939). The predicted NAD-binding site suggests that <i>A. ferrooxidans</i> can use NADPH as an electron donor, as has been shown for <i>Pyrococcus furiosus</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 69" title="Ma K, Adams MW: Sulfide dehydrogenase from the hyperthermophilic archaeon Pyrococcus furiosus: a new multifunctional enzyme involved in the reduction of elemental sulfur. J Bacteriol. 1994, 176 (21): 6509-6517." href="/articles/10.1186/1471-2164-9-597#ref-CR69" id="ref-link-section-d25988610e1722">69</a>]. A possible role for this hydrogenase could be the recycling of redox cofactors using protons or water as redox counterparts, as has been suggested for <i>Alcaligenes eutrophus</i>, thus serving as an electron sink under high reducing conditions [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 66" title="Lenz O, Friedrich B: A novel multicomponent regulatory system mediates H2 sensing in Alcaligenes eutrophus. Proc Natl Acad Sci USA. 1998, 95 (21): 12474-12479. 10.1073/pnas.95.21.12474." href="/articles/10.1186/1471-2164-9-597#ref-CR66" id="ref-link-section-d25988610e1729">66</a>].</p><p>The gene organization and amino acid sequence of a six-gene cluster (AFE2149-54) (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-2164-9-597#Fig4">4c</a>) shows significant similarity to the group 4 H<sub>2</sub>-evolving hydrogenase complex found in several organisms (e.g., <i>Methanococcus barkeri</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 70" title="Hedderich R: Energy-converting [NiFe] hydrogenases from archaea and extremophiles: ancestors of complex I. J Bioenerg Biomembr. 2004, 36 (1): 65-75. 10.1023/B:JOBB.0000019599.43969.33." href="/articles/10.1186/1471-2164-9-597#ref-CR70" id="ref-link-section-d25988610e1744">70</a>]). In <i>M. barkeri</i>, this cluster encodes a six-subunit complex that catalyzes the energetically unfavorable reduction of ferrodoxin by H<sub>2</sub>, possibly driven by reverse electron transport. The reduced ferrodoxin produced then serves as a low-potential electron donor for the synthesis of pyruvate in an anabolic pathway [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 71" title="Meuer J, Kuettner HC, Zhang JK, Hedderich R, Metcalf WW: Genetic analysis of the archaeon Methanosarcina barkeri Fusaro reveals a central role for Ech hydrogenase and ferredoxin in methanogenesis and carbon fixation. Proc Natl Acad Sci USA. 2002, 99 (8): 5632-5637. 10.1073/pnas.072615499." href="/articles/10.1186/1471-2164-9-597#ref-CR71" id="ref-link-section-d25988610e1753">71</a>]. Reverse electron flow for the production of NADH via the oxidation of Fe(II) in <i>A. ferrooxidans</i> has been shown to be driven by the proton motif force (PMF) across its membrane that results from the acidity of its environment [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 72" title="Brasseur G, Bruscella P, Bonnefoy V, Lemesle-Meunier D: The bc(1) complex of the iron-grown acidophilic chemolithotrophic bacterium Acidithiobacillus ferrooxidans functions in the reverse but not in the forward direction. Is there a second bc(1) complex?. Biochim Biophys Acta. 2002, 1555 (1–3): 37-43." href="/articles/10.1186/1471-2164-9-597#ref-CR72" id="ref-link-section-d25988610e1759">72</a>]. The predicted activity of the group 4 hydrogenase complex may exemplify another where <i>A. ferrooxidans</i> exploits the natural PMF to generate reducing power and couple it to redox reactions.</p><p>Another possible role for the group 4 hydrogenase complex involves the oxidation of formate. Two clusters of three genes (AFE1652-4 and AFE0690-2) potentially encode a formate dehydrogenase complex consisting of a formate dehydrogenase accessory protein FdhD-1, a hypothetical protein, and a molybdopterin formate dehydrogenase. The second cluster is divergently oriented from a gene encoding a predicted σ<sub>54</sub>-dependent transcriptional regulator. It has been reported that this complex associates with a hydrogenase group 4 complex in <i>E. coli</i> to create a formate hydrogenase supercomplex [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 73" title="Andrews SC, Berks BC, McClay J, Ambler A, Quail MA, Golby P, Guest JR: A 12-cistron Escherichia coli operon (hyf) encoding a putative proton-translocating formate hydrogenlyase system. Microbiology. 1997, 143 (Pt 11): 3633-3647." href="/articles/10.1186/1471-2164-9-597#ref-CR73" id="ref-link-section-d25988610e1773">73</a>]. We propose a similar model for <i>A. ferrooxidans</i>, thus offering a biochemical basis for its ability to oxidize formate [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Pronk JT, Meijer WM, Hazeu W, van Dijken JP, Bos P, Kuenen JG: Growth of Thiobacillus ferrooxidans on Formic Acid. Appl Environ Microbiol. 1991, 57 (7): 2057-2062." href="/articles/10.1186/1471-2164-9-597#ref-CR10" id="ref-link-section-d25988610e1779">10</a>].</p><h5 class="c-article__sub-heading c-article__sub-heading--small" id="Sec10">2.2.4 Anaerobic metabolism</h5><p>Several strains of <i>A. ferrooxidans</i> have been reported to use electron acceptors other than O<sub>2</sub>, including the use of ferric iron for the oxidation of sulfur and hydrogen and the use of sulfur for the oxidation of hydrogen by <i>A. ferrooxidans</i> JCM 7811 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 74" title="Ohmura N, Sasaki K, Matsumoto N, Saiki H: Anaerobic respiration using Fe(3+), S(0), and H(2) in the chemolithoautotrophic bacterium Acidithiobacillus ferrooxidans. J Bacteriol. 2002, 184 (8): 2081-2087. 10.1128/JB.184.8.2081-2087.2002." href="/articles/10.1186/1471-2164-9-597#ref-CR74" id="ref-link-section-d25988610e1798">74</a>]. In that strain, the reduction of ferric iron was accompanied by the increased expression of a 28 kDa c-type cytochrome that was suggested to be responsible for this activity [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 74" title="Ohmura N, Sasaki K, Matsumoto N, Saiki H: Anaerobic respiration using Fe(3+), S(0), and H(2) in the chemolithoautotrophic bacterium Acidithiobacillus ferrooxidans. J Bacteriol. 2002, 184 (8): 2081-2087. 10.1128/JB.184.8.2081-2087.2002." href="/articles/10.1186/1471-2164-9-597#ref-CR74" id="ref-link-section-d25988610e1801">74</a>]. The reduction of ferric iron during sulfur oxidation was also shown for the type strain ATCC 23270 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 75" title="Pronk JT, de Bruyn JC, Bos P, Kuenen JG: Anaerobic Growth of Thiobacillus ferrooxidans. Appl Environ Microbiol. 1992, 58 (7): 2227-2230." href="/articles/10.1186/1471-2164-9-597#ref-CR75" id="ref-link-section-d25988610e1805">75</a>]. However, a gene potentially encoding this cytochrome could not be identified in <i>A. ferrooxidans</i> ATCC 23270 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 76" title="Yarzabal A, Brasseur G, Bonnefoy V: Cytochromes c of Acidithiobacillus ferrooxidans. FEMS Microbiol Lett. 2002, 209 (2): 189-195." href="/articles/10.1186/1471-2164-9-597#ref-CR76" id="ref-link-section-d25988610e1811">76</a>]. A candidate iron reduction complex has been investigated in <i>A. ferrooxidans</i> AP19-3 by electrophoretic purification and enzymatic assays [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 77" title="Sugio T, Mizunashi W, Inagaki K, Tano T: Purification and some properties of sulfur:ferric ion oxidoreductase from Thiobacillus ferrooxidans. J Bacteriol. 1987, 169 (11): 4916-4922." href="/articles/10.1186/1471-2164-9-597#ref-CR77" id="ref-link-section-d25988610e1817">77</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 78" title="Sugio T, Hirose T, Ye LZ, Tano T: Purification and some properties of sulfite:ferric ion oxidoreductase from Thiobacillus ferrooxidans. J Bacteriol. 1992, 174 (12): 4189-4192." href="/articles/10.1186/1471-2164-9-597#ref-CR78" id="ref-link-section-d25988610e1820">78</a>]. However, potential genes encoding this complex could not be detected in our genome analysis.</p><p>The use of sulfur as an electron acceptor was investigated in <i>A. ferrooxidans</i> NASF-1 where aerobically grown cells were found to produce hydrogen sulfide from elemental sulfur using NADH as electron donor via a proposed sulfur reductase [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 79" title="Ng KY, Sawada R, Inoue S, Kamimura K, Sugio T: Purification and some properties of sulfur reductase from the iron-oxidizing bacterium Thiobacillus ferrooxidans NASF-1. J Biosci Bioeng. 2000, 90 (2): 199-203. 10.1016/S1389-1723(00)80110-3." href="/articles/10.1186/1471-2164-9-597#ref-CR79" id="ref-link-section-d25988610e1829">79</a>]. However, the observed molecular weights of the subunits of this sulfur reductase do not correspond to those predicted from an analysis of the group 3b hydrogenase genes in the type strain genome, with the caveat that post-translational modifications could explain the differences in molecular weights. However, a gene cluster (AFE2177-81) was detected in the type strain that is predicted to encode a sulfur reductase enzyme with significant similarity of amino acid sequence and gene order to the cluster suggested to be responsible for sulfur reduction in <i>Acidianus ambivalens</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 80" title="Laska S, Lottspeich F, Kletzin A: Membrane-bound hydrogenase and sulfur reductase of the hyperthermophilic and acidophilic archaeon Acidianus ambivalens. Microbiology. 2003, 149 (Pt 9): 2357-2371. 10.1099/mic.0.26455-0." href="/articles/10.1186/1471-2164-9-597#ref-CR80" id="ref-link-section-d25988610e1835">80</a>]. We hypothesize that this enzyme could associate with the predicted group 1 hydrogenase to form a supercomplex, facilitating the use of hydrogen as an electron and energy source with sulfur serving as the final electron acceptor.</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec11">2.3 Nitrogen metabolism</h4><p><i>A. ferrooxidans</i> can meet its nitrogen needs by either nitrogen fixation or ammonia assimilation. Diazotrophic growth of <i>A. ferrooxidans</i> was first demonstrated in early studies of acetylene reduction and <sup>15</sup>N<sub>2</sub> assimilation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="Makcintosh MW: Nitrogen fixation by Thiobacillus ferrooxidans. J Gen Microbiol. 1978, 34 (105): 215-218." href="/articles/10.1186/1471-2164-9-597#ref-CR15" id="ref-link-section-d25988610e1856">15</a>] and the structural genes for the nitrogenase complex were later sequenced [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 81" title="Pretorius IM, Rawlings DE, Woods DR: Identification and cloning of Thiobacillus ferrooxidans structural nif genes in Escherichia coli. Gene. 1986, 45 (1): 59-65. 10.1016/0378-1119(86)90132-0." href="/articles/10.1186/1471-2164-9-597#ref-CR81" id="ref-link-section-d25988610e1859">81</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 83" title="Rawlings DE: Sequence and structural analysis of the alpha- and beta-dinitrogenase subunits of Thiobacillus ferrooxidans. Gene. 1988, 69 (2): 337-343. 10.1016/0378-1119(88)90444-1." href="/articles/10.1186/1471-2164-9-597#ref-CR83" id="ref-link-section-d25988610e1863">83</a>].</p><h5 class="c-article__sub-heading c-article__sub-heading--small" id="Sec12">2.3.1 Ammonia uptake and utilization</h5><p>The <i>A. ferrooxidans</i> genome contains genes predicted to be involved in ammonia uptake (<i>amt1</i>, <i>amt2</i> and <i>amtB</i>; AFE2916, AFE2911, and AFE1922). <i>Amt1</i> and <i>amt2</i> are located in a gene cluster that includes a gene potentially encoding a class-I glutamine amidotransferase (AFE2917) that has been shown in other organisms to transfer ammonia derived from the hydrolysis of glutamine to other substrates. <i>GlnK-1</i> (AFE2915) is also present in this cluster and is predicted to encode a P-II regulatory protein involved in the regulation of nitrogen metabolism in response to carbon and glutamine availability [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 84" title="Dixon R, Kahn D: Genetic regulation of biological nitrogen fixation. Nat Rev Microbiol. 2004, 2 (8): 621-631. 10.1038/nrmicro954." href="/articles/10.1186/1471-2164-9-597#ref-CR84" id="ref-link-section-d25988610e1895">84</a>]. A <i>glnA</i> homolog (AFE0466) is predicted to encode a type I glutamine synthase that would permit the incorporation of ammonia directly into glutamine, completing the inventory of genes necessary for ammonia uptake and utilization.</p><h5 class="c-article__sub-heading c-article__sub-heading--small" id="Sec13">2.3.2 Nitrogen Fixation</h5><p>A putative nitrogenase gene cluster (<i>nifH-D-K-fer1-fer2-E-N-X</i>; AFE1522-AFE1515) (Additional file <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/10.1186/1471-2164-9-597#MOESM4">4</a>) was previously reported in the type strain [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 68" title="Valdes J, Veloso F, Jedlicki E, Holmes D: Metabolic reconstruction of sulfur assimilation in the extremophile Acidithiobacillus ferrooxidans based on genome analysis. BMC Genomics. 2003, 4 (1): 51-10.1186/1471-2164-4-51." href="/articles/10.1186/1471-2164-9-597#ref-CR68" id="ref-link-section-d25988610e1915">68</a>]. These genes potentially encode the nitrogenase complex and proteins involved in the synthesis of the nitrogenase MoCo cofactor. In other organisms, nitrogenase has been shown to be oxygen sensitive and its expression and activity are regulated at both the transcriptional and post-translational levels [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 84" title="Dixon R, Kahn D: Genetic regulation of biological nitrogen fixation. Nat Rev Microbiol. 2004, 2 (8): 621-631. 10.1038/nrmicro954." href="/articles/10.1186/1471-2164-9-597#ref-CR84" id="ref-link-section-d25988610e1918">84</a>]. Divergently oriented from the <i>nif</i> operon is a cluster of genes involved in the regulation of nitrogenase activity. The first gene of this cluster is a putative σ<sub>54</sub> response regulator (AFE1523). This is followed by the <i>draT</i> and <i>draG</i> genes (AFE1524, AFE1525) that encode a dinitrogen-reductase ADP-D-ribosyltransferase and a ADP-ribosyl-[dinitrogen reductase] hydrolase, respectively. These two are involved in the post-translational modulation of nitrogenase activity in response to ammonium and oxygen concentrations [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 84" title="Dixon R, Kahn D: Genetic regulation of biological nitrogen fixation. Nat Rev Microbiol. 2004, 2 (8): 621-631. 10.1038/nrmicro954." href="/articles/10.1186/1471-2164-9-597#ref-CR84" id="ref-link-section-d25988610e1933">84</a>]. <i>NifA</i> (AFE1527) is also present in the same gene cluster. <i>NifA</i> potentially encodes an enhancer binding protein that, together with σ<sub>54</sub>, is involved in the transcriptional activation of the <i>nif</i> operon in response to the redox, carbon, and nitrogen status. This ensures that nitrogen fixation occurs only under physiological conditions that are appropriate for nitrogenase activity [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 85" title="Little R, Martinez-Argudo I, Dixon R: Role of the central region of NifL in conformational switches that regulate nitrogen fixation. Biochem Soc Trans. 2006, 34 (Pt 1): 162-164." href="/articles/10.1186/1471-2164-9-597#ref-CR85" id="ref-link-section-d25988610e1948">85</a>].</p><p>Using this genomic information, a gene network for the regulation of nitrogen fixation and ammonia uptake can be suggested for <i>A. ferrooxidans</i> that is consistent with similar models derived from other organisms (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-2164-9-597#Fig5">5</a>) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 84" title="Dixon R, Kahn D: Genetic regulation of biological nitrogen fixation. Nat Rev Microbiol. 2004, 2 (8): 621-631. 10.1038/nrmicro954." href="/articles/10.1186/1471-2164-9-597#ref-CR84" id="ref-link-section-d25988610e1960">84</a>]. In this model, NifA (AFE1527) is the transcriptional activator of the nitrogenase operon and its expression is regulated by a two-component regulatory system encoded by <i>ntrB</i> and <i>ntrC</i> (AFE2902, AFE2901) that measure oxygen and nitrogen levels. These signals are integrated by the P-II proteins (<i>glnK-1</i>, AFE2915; <i>glnB-1</i>, AFE2462; <i>glnK-2</i>, AFE2240; and <i>glnB-2</i>, AFE0429) with additional metabolic signals, such as fixed carbon and energetic status [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 86" title="Forchhammer K: P(II) signal transducers: novel functional and structural insights. Trends Microbiol. 2008, 16 (2): 65-72." href="/articles/10.1186/1471-2164-9-597#ref-CR86" id="ref-link-section-d25988610e1982">86</a>]. Two additional copies of <i>ntrC</i> and <i>ntrB</i>, termed <i>ntrY</i> and <i>ntrX</i> (AFE0024, AFE0023) have been detected in the genome that could allow cross talk between the sensor/regulator pairs NtrY/X and NtrB/C, as described in <i>Azospirillum brasilense</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 87" title="Ishida ML, Assumpcao MC, Machado HB, Benelli EM, Souza EM, Pedrosa FO: Identification and characterization of the two-component NtrY/NtrX regulatory system in Azospirillum brasilense. Braz J Med Biol Res. 2002, 35 (6): 651-661. 10.1590/S0100-879X2002000600004." href="/articles/10.1186/1471-2164-9-597#ref-CR87" id="ref-link-section-d25988610e2001">87</a>]. The redundancy of the regulatory genes responsible for nitrogen fixation and assimilation suggests the presence of a flexible mechanism that is responsive to environmental changes.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-5" data-title="Figure 5"><figure><figcaption><b id="Fig5" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 5</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.1186/1471-2164-9-597/figures/5" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig5_HTML.jpg?as=webp"><img aria-describedby="Fig5" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig5_HTML.jpg" alt="figure 5" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-5-desc"><p><b>Predicted regulatory models for inorganic ion uptake and assimilation</b>. A) Phosphate and phosphonate. B) Nitrogen and ammonia. C) Ferric and ferrous iron. D) Sulfate. Proteins and protein complexes are described in the text.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.1186/1471-2164-9-597/figures/5" data-track-dest="link:Figure5 Full size image" aria-label="Full size image figure 5" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><h3 class="c-article__sub-heading" id="Sec14">3. Nutrient uptake and assimilation systems</h3><p><i>A. ferrooxidans</i> has 72 genes (2.23%) predicted to be involved in nutrient uptake (Additional file <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/10.1186/1471-2164-9-597#MOESM3">3</a>) whereas most heterotrophic γ-proteobacteria typically dedicate about 14% of their genome information to transport functions [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 88" title="Scott KM, Sievert SM, Abril FN, Ball LA, Barrett CJ, Blake RA, Boller AJ, Chain PS, Clark JA, Davis CR: The genome of deep-sea vent chemolithoautotroph Thiomicrospira crunogena XCL-2. PLoS Biol. 2006, 4 (12): e383-10.1371/journal.pbio.0040383." href="/articles/10.1186/1471-2164-9-597#ref-CR88" id="ref-link-section-d25988610e2039">88</a>]. The potential substrates incorporated include phosphate, sulfate, iron, ammonia, organic acids, amino acids, and sugars. This repertoire, especially the low representation of predicted carbohydrate uptake systems, is a signature of obligate autotrophic bacteria [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 88" title="Scott KM, Sievert SM, Abril FN, Ball LA, Barrett CJ, Blake RA, Boller AJ, Chain PS, Clark JA, Davis CR: The genome of deep-sea vent chemolithoautotroph Thiomicrospira crunogena XCL-2. PLoS Biol. 2006, 4 (12): e383-10.1371/journal.pbio.0040383." href="/articles/10.1186/1471-2164-9-597#ref-CR88" id="ref-link-section-d25988610e2042">88</a>].</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec15">3.1 Inorganic ion assimilation</h4><h5 class="c-article__sub-heading c-article__sub-heading--small" id="Sec16">3.1.1 Sulfate</h5><p>A gene for a predicted sulfate permease (AFE0286) of the SulP family is present in the genome adjacent to a potential carbonic anhydrase gene (AFE0287). This linkage has been observed in many bacteria [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 89" title="Felce J, Saier MH: Carbonic anhydrases fused to anion transporters of the SulP family: evidence for a novel type of bicarbonate transporter. J Mol Microbiol Biotechnol. 2004, 8 (3): 169-176. 10.1159/000085789." href="/articles/10.1186/1471-2164-9-597#ref-CR89" id="ref-link-section-d25988610e2056">89</a>], suggesting that the gene pair forms a sulfate/carbonate antiporter system. Sulfate taken up from the environment is thought to be reduced to sulfide for cysteine biosynthesis by a group of genes belonging to the <i>cys</i> regulon [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 68" title="Valdes J, Veloso F, Jedlicki E, Holmes D: Metabolic reconstruction of sulfur assimilation in the extremophile Acidithiobacillus ferrooxidans based on genome analysis. BMC Genomics. 2003, 4 (1): 51-10.1186/1471-2164-4-51." href="/articles/10.1186/1471-2164-9-597#ref-CR68" id="ref-link-section-d25988610e2062">68</a>].</p><h5 class="c-article__sub-heading c-article__sub-heading--small" id="Sec17">3.1.2 Phosphate</h5><p>Previous investigations of phosphate metabolism in <i>A. ferrooxidans</i> provided evidence for a phosphate starvation response [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 90" title="Seeger M, Jerez CA: Phosphate-starvation induced changes in Thiobacillus ferrooxidans. FEMS Microbiol Lett. 1993, 108 (1): 35-41. 10.1111/j.1574-6968.1993.tb06070.x." href="/articles/10.1186/1471-2164-9-597#ref-CR90" id="ref-link-section-d25988610e2076">90</a>] and for a relationship between polyphosphate degradation and heavy metal resistance and efflux [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 91" title="Alvarez S, Jerez CA: Copper ions stimulate polyphosphate degradation and phosphate efflux in Acidithiobacillus ferrooxidans. Appl Environ Microbiol. 2004, 70 (9): 5177-5182. 10.1128/AEM.70.9.5177-5182.2004." href="/articles/10.1186/1471-2164-9-597#ref-CR91" id="ref-link-section-d25988610e2079">91</a>]. However, we still lacked a comprehensive understanding of all the potential components involved in phosphate metabolism, as well as their integration and regulation. Our genome analysis identified a complete repertoire of the genes necessary for phosphate uptake by the high affinity Pst-transport system. These predicted genes are arranged in two similar clusters. The first cluster (AFE1939-41) includes two genes (<i>pstC-1</i> and <i>pstC-2</i>) that encode a phosphate permease and a third gene (<i>pstS-1</i>) that encodes a periplasmic phosphate binding protein. The second gene cluster (AFE1441-1434) includes a gene encoding a exopolyphosphatase (<i>ppx</i>, AFE1441) previously described to be involved in heavy metal resistance and efflux [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 91" title="Alvarez S, Jerez CA: Copper ions stimulate polyphosphate degradation and phosphate efflux in Acidithiobacillus ferrooxidans. Appl Environ Microbiol. 2004, 70 (9): 5177-5182. 10.1128/AEM.70.9.5177-5182.2004." href="/articles/10.1186/1471-2164-9-597#ref-CR91" id="ref-link-section-d25988610e2095">91</a>], <i>phoU</i> (AFE1440) predicted to encode a phosphate transport regulatory protein, <i>pstB</i> encoding an ATP binding protein, and <i>pstA</i> coding for the permease component. In addition, there are genes encoding a third homolog of the phosphate permease PstC-3, a second homolog of the periplasmic phosphate binding protein PstS-2, and the two-component response regulator PhoR/PhoB.</p><p>The predicted phosphonate utilization gene cluster (AFE2278-86) contains genes for C-P cleavage and an ATP-binding protein for the ABC phosphonate transport system. In spite of the experimental evidence reported about the utilization of phosphonate in this bacterium [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 92" title="Vera M, Pagliai F, Guiliani N, Jerez CA: The chemolithoautotroph Acidithiobacillus ferrooxidans can survive under phosphate-limiting conditions by expressing a C-P lyase operon that allows it to grow on phosphonates. Appl Environ Microbiol. 2008, 74 (6): 1829-1835. 10.1128/AEM.02101-07." href="/articles/10.1186/1471-2164-9-597#ref-CR92" id="ref-link-section-d25988610e2110">92</a>], the typical permease subunit that is required to complete phosphonate uptake was not found in the genome.</p><p>The genome does contain a gene (AFE1876) for a predicted polyphosphate kinase (Ppk) involved in polyphosphate storage. It has been suggested to be part of a <i>pho</i> regulon whose expression is activated during phosphate starvation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 89" title="Felce J, Saier MH: Carbonic anhydrases fused to anion transporters of the SulP family: evidence for a novel type of bicarbonate transporter. J Mol Microbiol Biotechnol. 2004, 8 (3): 169-176. 10.1159/000085789." href="/articles/10.1186/1471-2164-9-597#ref-CR89" id="ref-link-section-d25988610e2119">89</a>] and in response to heavy metal toxicity [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 91" title="Alvarez S, Jerez CA: Copper ions stimulate polyphosphate degradation and phosphate efflux in Acidithiobacillus ferrooxidans. Appl Environ Microbiol. 2004, 70 (9): 5177-5182. 10.1128/AEM.70.9.5177-5182.2004." href="/articles/10.1186/1471-2164-9-597#ref-CR91" id="ref-link-section-d25988610e2122">91</a>].</p><h5 class="c-article__sub-heading c-article__sub-heading--small" id="Sec18">3.1.3 Iron</h5><p>Genomic evidence indicates that <i>A. ferrooxidans</i> relies on diverse standard iron uptake mechanisms to obtain both Fe(II) and Fe(III) (93). The type strain has candidate genes (AFE2523-AFE2525) potentially encoding the FeoABC Fe(II) inner-membrane transport system and an NRAMP dual Mn(II)/Fe(II) MntH-like transporter (AFE0105). Previously reported gene context analysis indicated that <i>feoA, feoB</i>, and <i>feoC</i> form part of an iron-regulated operon, along with an ORF (AFE2522) encoding a putative porin (designated <i>feoP</i>) that could facilitate entrance of Fe(II) into the periplasm [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 93" title="Quatrini R, Lefimil C, Veloso FA, Pedroso I, Holmes DS, Jedlicki E: Bioinformatic prediction and experimental verification of Fur-regulated genes in the extreme acidophile Acidithiobacillus ferrooxidans. Nucleic Acids Res. 2007, 35 (7): 2153-2166. 10.1093/nar/gkm068." href="/articles/10.1186/1471-2164-9-597#ref-CR93" id="ref-link-section-d25988610e2145">93</a>].</p><p><i>A. ferrooxidans</i> is typically confronted with an exceptionally high concentration of soluble iron in its acidic environment, as high as 10<sup>-1</sup>M compared to 10<sup>-16</sup> M in typical neutrophilic environments. This raises questions as to the mechanisms it uses for iron assimilation and homeostatic control of internal iron concentrations. Given the abundance of both Fe(II) and Fe(III) in its environment, <i>A. ferrooxidans</i> has a surprisingly large number of iron uptake systems, including eleven distinct putative genes encoding TonB-dependent outer membrane receptors (<i>tdr</i>) for high affinity uptake of siderophore-chelated Fe(III) (<i>tdrA</i>, AFE2935; <i>tdrC</i>, AFE1483; <i>tdrD</i>, AFE1492; <i>tdrE</i>, AFE2040; <i>tdrF</i>, AFE2998; <i>tdrG</i>, AFE2302; <i>tdrH</i>, AFE2298; <i>tdrI</i>, AFE2292; <i>tdrJ</i>, AFE2288; <i>tdrK</i>, AFE0763; <i>tdrL</i>, AFE3229). Also, it has a number of copies of all the accessory genes needed to transport iron into the cytoplasm, including seven different copies of the energy transduction genes <i>tonB</i> (AFE3002, AFE2304, AFE2301, AFE2275, AFE2268, AFE1487, AFE0770) and <i>exbB</i> (AFE3003, AFE2299, AFE2273, AFE2270, AFE1485, AFE0768, AFE0485) and six copies of <i>exbD</i> (AFE3004, AFE2300, AFE2269, AFE1486, AFE0769, AFE0486), as well as the genes encoding two different ABC iron transporters (AFE1489-AFE1491, AFE1493-AFE1495). No genes were detected that might be involved in standard mechanisms of siderophore production. However, its multiple siderophore uptake systems suggest that it is nonetheless capable of living in environments where iron is scarce (perhaps at higher pH values) and in which other organisms capable of producing siderophores are present.</p><p>For Fe(III) uptake, all the genes involved are organized in seven gene clusters, some of which include additional gene functions [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Quatrini R, Jedlicki E, Holmes DS: Genomic insights into the iron uptake mechanisms of the biomining microorganism Acidithiobacillus ferrooxidans. J Ind Microbiol Biotechnol. 2005, 32 (11–12): 606-614. 10.1007/s10295-005-0233-2." href="/articles/10.1186/1471-2164-9-597#ref-CR22" id="ref-link-section-d25988610e2211">22</a>]. One cluster encodes a complete suite of proteins necessary for Fe(III) uptake (AFE1482-AFE1495) that includes not only two outer membrane receptors (OMRs) of different predicted siderophore specificities, but also three different ABC solute-binding proteins with affinity for iron and molybdenum and may be a dedicated iron-molybdenum transport system that is present in a genomic island [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 94" title="Osorio H, Martínez V, Nieto PA, Holmes DS, Quatrini R: Microbial iron management mechanisms in extremely acidic environments: comparative genomics evidence for diversity and versatility. BMC Microbiology. 2008, 8 (1): 203-10.1186/1471-2180-8-203." href="/articles/10.1186/1471-2164-9-597#ref-CR94" id="ref-link-section-d25988610e2214">94</a>]. This predicted operon also includes a putative gene (<i>gloA</i>, AFE1482) predicted to encode a globin-like protein that has been suggested to be an oxygen sensor regulating the expression of Fe-Mo uptake [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 94" title="Osorio H, Martínez V, Nieto PA, Holmes DS, Quatrini R: Microbial iron management mechanisms in extremely acidic environments: comparative genomics evidence for diversity and versatility. BMC Microbiology. 2008, 8 (1): 203-10.1186/1471-2180-8-203." href="/articles/10.1186/1471-2164-9-597#ref-CR94" id="ref-link-section-d25988610e2220">94</a>]. GloA is also associated with an upstream Fur box, indicating possible regulation via the master iron regulator Fur [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Quatrini R, Lefimil C, Holmes DS, Jedlicki E: The ferric iron uptake regulator (Fur) from the extreme acidophile Acidithiobacillus ferrooxidans. Microbiology. 2005, 151 (Pt 6): 2005-2015. 10.1099/mic.0.27581-0." href="/articles/10.1186/1471-2164-9-597#ref-CR21" id="ref-link-section-d25988610e2223">21</a>].</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec19">3.2 Carbon compound uptake</h4><h5 class="c-article__sub-heading c-article__sub-heading--small" id="Sec20">3.2.1 Amino acids</h5><p>Among the predicted nutrient transport genes in the <i>A. ferrooxidans</i> genome are five amino acid permeases of unknown specificity (AFE2659, AFE2457, AFE1782, AFE0719, and AFE0439) (the same number as found in the chemolithoautotroph <i>T. crunogena</i>) and one complete ABC system for dipeptide uptake (AFE2987-92). The addition of leucine to solid media has been reported to improve the yield of <i>A. ferrooxidans</i> ATCC 33020 during the first ten days of growth, whereas the addition of cysteine or methionine inhibits growth [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 95" title="Liu Z, Borne F, Bonnefoy V: Genetic transfer of IncP, IncQ and IncW plasmids to four Thiobacillus ferrooxidans strains by conjugation. Hydrometallurgy. 2001, 59: 339-345. 10.1016/S0304-386X(00)00176-6." href="/articles/10.1186/1471-2164-9-597#ref-CR95" id="ref-link-section-d25988610e2248">95</a>]. More recently, the addition of minimal concentrations of glutamate to liquid media was found to accelerate the growth rate of <i>A. ferrooxidans</i> ATCC 23270 (Omar Orellana, personal communication).</p><h5 class="c-article__sub-heading c-article__sub-heading--small" id="Sec21">3.2.2 Carbohydrate uptake</h5><p>The suite of genes for carbohydrate transport appears to be limited, as has been found in most obligate autotrophs (e.g., <i>T. denitrificans</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 96" title="Beller HR, Letain TE, Chakicherla A, Kane SR, Legler TC, Coleman MA: Whole-genome transcriptional analysis of chemolithoautotrophic thiosulfate oxidation by Thiobacillus denitrificans under aerobic versus denitrifying conditions. J Bacteriol. 2006, 188 (19): 7005-7015. 10.1128/JB.00568-06." href="/articles/10.1186/1471-2164-9-597#ref-CR96" id="ref-link-section-d25988610e2265">96</a>], <i>T. crunogena</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 88" title="Scott KM, Sievert SM, Abril FN, Ball LA, Barrett CJ, Blake RA, Boller AJ, Chain PS, Clark JA, Davis CR: The genome of deep-sea vent chemolithoautotroph Thiomicrospira crunogena XCL-2. PLoS Biol. 2006, 4 (12): e383-10.1371/journal.pbio.0040383." href="/articles/10.1186/1471-2164-9-597#ref-CR88" id="ref-link-section-d25988610e2271">88</a>], <i>M. capsulatus</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 97" title="Ward N, Larsen O, Sakwa J, Bruseth L, Khouri H, Durkin AS, Dimitrov G, Jiang L, Scanlan D, Kang KH: Genomic insights into methanotrophy: the complete genome sequence of Methylococcus capsulatus (Bath). PLoS Biol. 2004, 2 (10): e303-10.1371/journal.pbio.0020303." href="/articles/10.1186/1471-2164-9-597#ref-CR97" id="ref-link-section-d25988610e2278">97</a>], <i>N. europea</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 98" title="Chain P, Lamerdin J, Larimer F, Regala W, Lao V, Land M, Hauser L, Hooper A, Klotz M, Norton J: Complete genome sequence of the ammonia-oxidizing bacterium and obligate chemolithoautotroph Nitrosomonas europaea. J Bacteriol. 2003, 185 (9): 2759-2773. 10.1128/JB.185.9.2759-2773.2003." href="/articles/10.1186/1471-2164-9-597#ref-CR98" id="ref-link-section-d25988610e2284">98</a>], and <i>N. oceanii</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 99" title="Klotz MG, Arp DJ, Chain PS, El-Sheikh AF, Hauser LJ, Hommes NG, Larimer FW, Malfatti SA, Norton JM, Poret-Peterson AT: Complete genome sequence of the marine, chemolithoautotrophic, ammonia-oxidizing bacterium Nitrosococcus oceani ATCC 19707. Appl Environ Microbiol. 2006, 72 (9): 6299-6315. 10.1128/AEM.00463-06." href="/articles/10.1186/1471-2164-9-597#ref-CR99" id="ref-link-section-d25988610e2290">99</a>]). This suite of predicted genes includes two outer membrane carbohydrate selective porins of the OPRB family (AFE2522, AFE2250), one carbohydrate transporter of unknown specificity (AFE2312) that is related to the major facilitator superfamily (PF00083, PS50850) and very similar to xylose and galactose proton symporters [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 100" title="Barreto M, Jedlicki E, Holmes DS: Identification of a gene cluster for the formation of extracellular polysaccharide precursors in the chemolithoautotroph Acidithiobacillus ferrooxidans. Appl Environ Microbiol. 2005, 71 (6): 2902-2909. 10.1128/AEM.71.6.2902-2909.2005." href="/articles/10.1186/1471-2164-9-597#ref-CR100" id="ref-link-section-d25988610e2293">100</a>], and an MFS transporter (AFE1971) with marginal similarity to sugar/nucleoside symporters. It also includes genes for an incomplete PTS system for carbohydrate uptake (AFE3018-23) potentially encoding EII-A, a kinase/phosphatase HprK, an ATPase, an IIA component, a phosphocarrier protein Hpr, and a phosphoenolpyruvate phosphotransferase. However, we could not identify a gene encoding the IIC sugar permease component, thus making it unlikely that <i>A. ferrooxidans</i> has a functional sugar-transporting PTS system. Instead, we suggest that this PTS system could be involved in molecular signaling as part of a regulatory cascade involving RpoN, as described in other proteobacteria [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 101" title="Boel G, Mijakovic I, Maze A, Poncet S, Taha MK, Larribe M, Darbon E, Khemiri A, Galinier A, Deutscher J: Transcription regulators potentially controlled by HPr kinase/phosphorylase in Gram-negative bacteria. J Mol Microbiol Biotechnol. 2003, 5 (4): 206-215. 10.1159/000071072." href="/articles/10.1186/1471-2164-9-597#ref-CR101" id="ref-link-section-d25988610e2300">101</a>]. In this model, a decrease of fixed carbon leads to low levels of phosphoenolpyruvate and cyclic-AMP that in turn maintain most PTS proteins in the dephosphorylated form. This promotes the utilization of glycogen as a carbon source to replenish the phosphoenolpyruvate levels, thus restoring the levels of phosphorylated PTS proteins [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 102" title="Deutscher J, Francke C, Postma PW: How phosphotransferase system-related protein phosphorylation regulates carbohydrate metabolism in bacteria. Microbiol Mol Biol Rev. 2006, 70 (4): 939-1031. 10.1128/MMBR.00024-06." href="/articles/10.1186/1471-2164-9-597#ref-CR102" id="ref-link-section-d25988610e2303">102</a>].</p><h3 class="c-article__sub-heading" id="Sec22">4. Central carbon metabolism</h3><p>It has been shown in many organisms that the 3-phosphoglyceraldehyde generated by CO<sub>2</sub> fixation via the Calvin cycle enters the Embden-Meyerhof-Parnass pathway, thus providing fixed carbon that can be channeled in either of two directions: for glycogen biosynthesis and storage, or to provide carbon backbones for anabolic reactions. The genes predicted for these two pathways in <i>A. ferrooxidans</i>, together with their reactions and potential interconnections with other biosynthetic pathways, are shown in Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-2164-9-597#Fig6">6</a>.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-6" data-title="Figure 6"><figure><figcaption><b id="Fig6" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 6</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.1186/1471-2164-9-597/figures/6" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig6_HTML.jpg?as=webp"><img aria-describedby="Fig6" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig6_HTML.jpg" alt="figure 6" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-6-desc"><p> <b>Predicted pathways (pentose phosphate pathway, glycolysis, glycogen and interrupted TCA cycle) for central carbon metabolism.</b> </p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.1186/1471-2164-9-597/figures/6" data-track-dest="link:Figure6 Full size image" aria-label="Full size image figure 6" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec23">4.1 Carbon storage and utilization</h4><p>The genome also contains genes predicted to encode the five enzymes required for glycogen biosynthesis from fructose-6P. As has been shown in other organisms, glucose-1P-adenylyltransferase (<i>glgC</i>, AFE2838) is predicted to synthesize ADP-glucose. A specific glycogen synthase (<i>glgA</i>, AFE2678) would then transfer the glucosyl moiety of ADP-glucose to a glycogen primer to form a new 1,4-glucosidic bond. Subsequently, a branching enzyme (<i>glgB</i>, AFE2836) is predicted to catalyze the formation of branched 1,6-glucosidic linkages.</p><p>The carbon stored in glycogen is thought to be released by glucan phosphorylase (<i>glgP1</i>, AFE1799; <i>glgP2</i>, AFE0527), thus regenerating glucose-1P from the non-reducing terminus of the 1,4 chain. The pathway for the conversion of glucose-6P to 2-dehydro-3-deoxy-gluconate is also predicted to be present, except for the last step that replenishes the levels of pyruvate and 3P-glycerate. In addition, a gene encoding phosphoribulokinase was not detected, thus suggesting that either alternate genes encode the missing functions or else that <i>A. ferrooxidans</i> regenerates pyruvate and 3P-glycerate from stored glycogen by alternate pathways. Expression data obtained from <i>A. ferrooxidans</i> growing with sulfur and iron as energy sources have shown that genes involved in glycogen synthesis and utilization are differentially expressed [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 103" title="Appia-Ayme C, Quatrini R, Dennis Y, Denizot F, Silver S, Roberto F, Veloso F, Valdes J, Cardenas J, Esparza M: Microarray and bioinformatic analyses suggest models for carbon metabolism in the autotroph Acidithiobacillus ferrooxidans. Hydrometallurgy. 2006, 83 (1–4): 273-280. 10.1016/j.hydromet.2006.03.029." href="/articles/10.1186/1471-2164-9-597#ref-CR103" id="ref-link-section-d25988610e2376">103</a>]. Specifically, growth in sulfur-containing media preferentially activates genes involved in glycogen biosynthesis, whereas growth on iron-supplemented media upregulates genes involved in glycogen breakdown. This suggests that <i>A. ferrooxidans</i> channels fixed carbon to glycogen when sulfur is available as an energy source and uses glycogen as a reserve carbon donor when iron is the energy source.</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec24">4.2 Carbon backbone formation</h4><p>The genome contains three genes (AFE1802, AFE1676 and AFE3248) that are predicted to encode fructose biphosphate aldolase (EC. 4.1.2.13), the enzyme that catalyzes the formation of fructose-1,6-bP. The interconversion of fructose-1,6-bP to fructose-6P in most heterotrophic bacteria is carried out by fructose biphosphatase and phosphofructokinase enzymes. In <i>A. ferrooxidans</i>, a gene encoding a fructose biphosphatase enzyme was found (AFE0189) that we suggest allows a direct flux of fixed carbon to glycogen storage. A potential phosphofructokinase candidate gene (AFE1807) was also found, a member of the PfkB family of sugar kinases (cd01164). It is located near putative genes involved in glycolysis/glyconeogenesis (e.g., phosphoglycerate mutase and phosphoenolpyruvate synthase), thus generating a bidirectional metabolic path for the utilization/generation of glycogen.</p><p>Putative genes for all the enzymes involved in the conversion of glyceraldehyde-3-P to pyruvate and acetyl-coA, as well as for the citric acid (TCA) cycle, were detected with the exception of genes encoding the E1-3 subunits of α-ketoglutarate dehydrogenase. Thus, the TCA cycle is incomplete, as has been described in a number of obligate autotrophic bacteria and archaea – a likely hallmark of this lifestyle [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 104" title="Wood AP, Aurikko JP, Kelly DP: A challenge for 21st century molecular biology and biochemistry: what are the causes of obligate autotrophy and methanotrophy?. FEMS Microbiol Rev. 2004, 28 (3): 335-352. 10.1016/j.femsre.2003.12.001." href="/articles/10.1186/1471-2164-9-597#ref-CR104" id="ref-link-section-d25988610e2397">104</a>].</p><h3 class="c-article__sub-heading" id="Sec25">5. Heavy metal resistance</h3><p>Bioleaching microorganisms, such as <i>A. ferrooxidans</i>, typically live in environments that have high concentrations of soluble heavy metals (e.g., arsenic, mercury, and silver), as well as unusually high concentrations of potentially toxic metals (e.g., copper and iron). This has prompted numerous studies of the mechanisms employed by <i>A. ferrooxidans</i> for metal resistance [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 105" title="Silver S, Phung le T: A bacterial view of the periodic table: genes and proteins for toxic inorganic ions. J Ind Microbiol Biotechnol. 2005, 32 (11–12): 587-605. 10.1007/s10295-005-0019-6." href="/articles/10.1186/1471-2164-9-597#ref-CR105" id="ref-link-section-d25988610e2416">105</a>]. In contrast to the genomic perspective presented herein, those investigations were conducted on multiple strains and thus do not provide a coherent view of the repertoire of heavy metal resistance genes present within one strain.</p><p>Our genome analysis confirmed the presence of a divergent gene cluster (AFE2857-60) previously identified as involved in arsenic resistance. The cluster includes genes encoding an arsenate reductase (ArsC), the arsenate repressor (ArsR), the divergently-oriented arsenate efflux pump (ArsB), and a hypothetical protein (ArsH). The <i>arsCRB</i> gene cluster was shown to confer resistance to arsenate, arsenite, and antimonium in <i>E. coli</i>, but the function of <i>arsH</i> is unknown [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 106" title="Butcher BG, Rawlings DE: The divergent chromosomal ars operon of Acidithiobacillus ferrooxidans is regulated by an atypical ArsR protein. Microbiology. 2002, 148 (Pt 12): 3983-3992." href="/articles/10.1186/1471-2164-9-597#ref-CR106" id="ref-link-section-d25988610e2431">106</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 107" title="Butcher BG, Deane SM, Rawlings DE: The chromosomal arsenic resistance genes of Thiobacillus ferrooxidans have an unusual arrangement and confer increased arsenic and antimony resistance to Escherichia coli. Appl Environ Microbiol. 2000, 66 (5): 1826-1833. 10.1128/AEM.66.5.1826-1833.2000." href="/articles/10.1186/1471-2164-9-597#ref-CR107" id="ref-link-section-d25988610e2434">107</a>].</p><p>Mercury resistance has been investigated in several strains of <i>A. ferrooxidans</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 108" title="Olson GJ, Porter FD, Rubinstein J, Silver S: Mercuric reductase enzyme from a mercury-volatilizing strain of Thiobacillus ferrooxidans. J Bacteriol. 1982, 151 (3): 1230-1236." href="/articles/10.1186/1471-2164-9-597#ref-CR108" id="ref-link-section-d25988610e2443">108</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 110" title="Takeuchi F, Sugio T: Volatilization and recovery of mercury from mercury-polluted soils and wastewaters using mercury-resistant Acidithiobacillus ferrooxidans strains SUG 2-2 and MON-1. Environ Sci. 2006, 13 (6): 305-316." href="/articles/10.1186/1471-2164-9-597#ref-CR110" id="ref-link-section-d25988610e2446">110</a>]. Genome analysis of the type strain identified three genes potentially encoding the well-described Mer components, i.e., the repressor accessory protein (MerD, AFE2483), the mercury reductase (MerA, AFE2481), and the mercuric ion transporter (MerC, AFE2480). Four candidate genes potentially encoding members of the family of MerR-like transcriptional regulators were also found (AFE2607, AFE2509, AFE1431, and AFE0373).</p><p>The <i>A. ferrooxidans</i> genome also contains several genes (Additional file <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/10.1186/1471-2164-9-597#MOESM3">3</a>) predicted to be part of heavy metal tolerance systems [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 111" title="Barreto M, Quatrini R, Bueno S, Arriagada C, Valdes J, Silver S, Jedlicki E, Holmes D: Aspects of the predicted physiology of Acidithiobacillus ferrooxidans deduced from an analysis of its partial genome sequence. Hydrometallurgy. 2003, 71 (1–2): 97-105. 10.1016/S0304-386X(03)00145-2." href="/articles/10.1186/1471-2164-9-597#ref-CR111" id="ref-link-section-d25988610e2458">111</a>], including genes for the copCD copper extrusion system, ten clusters of genes predicted to belong to the resistance-nodulation-cell division (RND) family of transporters, three genes encoding cation diffusion facilitator (CDF) proteins, three genes encoding copper translocating P-type ATPases, and two genes encoding other P-type ATPases of unknown specificity. These genome-based predictions offer new opportunities for experimental validation of heavy metal resistance in <i>A. ferrooxidans</i> and also provide new markers for detecting similar genes in other microorganisms</p><h3 class="c-article__sub-heading" id="Sec26">6. Extrusion of toxic organic compounds</h3><p>The ability to extrude toxic organic compounds is widespread, and our inspection of the <i>A. ferrooxidans</i> genome suggests that this bacterium is well equipped to deal with toxic organic molecules. Its genome contains a gene predicted to encode the toluene tolerance protein TtgD (AFE1830) as well as a cluster of proteins often associated with toluene resistance that includes a Tol-Pal-associated acyl-CoA thioesterase (AFE0063) and TolBARQ (AFE0064-67).</p><p>The genome also includes a predicted complete ABC gene cluster (AFE0158-63) involved in drug extrusion that has significant similarity to the toluene ABC resistance proteins reported in other organisms. Resistance to toluene/xylene and related aromatic hydrocarbons and organic solvents may be needed by <i>A. ferrooxidans</i> when growing in runoff from coal wastes where it might encounter aromatic hydrocarbons [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 112" title="Nicomrat D, Dick WA, Tuovinen OH: Microbial populations identified by fluorescence in situ hybridization in a constructed wetland treating acid coal mine drainage. J Environ Qual. 2006, 35 (4): 1329-1337. 10.2134/jeq2005.0325." href="/articles/10.1186/1471-2164-9-597#ref-CR112" id="ref-link-section-d25988610e2481">112</a>] or in bioleaching operation heaps that are irrigated with recycled water containing carboxylic acids and other organic compounds from solvent extraction operations [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 113" title="Dold B, Blowes D, Dickhout R, Spangenberg J, Pfeifer H: Low molecular weight carboxylic acids in oxidizing porphyry copper tailings. Environ Sci Technol. 2005, 39 (8): 2515-2521. 10.1021/es040082h." href="/articles/10.1186/1471-2164-9-597#ref-CR113" id="ref-link-section-d25988610e2484">113</a>].</p><p>An alternative hypothesis for the role of drug-related compound extrusion mechanisms present in microbes associated with biogeochemical cycles has been proposed [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 114" title="Newman DK: From iron oxides to infections. Geobiology. 2008, 6 (3): 196-200. 10.1111/j.1472-4669.2008.00155.x." href="/articles/10.1186/1471-2164-9-597#ref-CR114" id="ref-link-section-d25988610e2490">114</a>]. A homolog of TolC has been shown in <i>Shewanella oneidensis</i> MR-1 to excrete anthraquinone-2,6-disulfonate (AQDS) that is used as an extracellular electron shuttle. It has been proposed that AQDS may be particularly important to transfer electrons from cells embedded in the interior of biofilms to reduce Fe(III) present in the solid substrate to which the biofilm is attached. It is possible that a similar mechanism may be used by <i>A. ferrooxidans</i> in the reverse process, namely, to convey electrons from the oxidation of Fe(II) present in solid minerals to cells not in contact with the substrate.</p><p>Two additional ABC systems potentially involved in drug extrusion are also predicted in the genome, each associated with a HlyD secretion protein family (AFE2861-64, AFE1603-7). The first is directly downstream from the <i>ars</i> genes; the second cluster may have originated through lateral gene transfer since it is flanked by truncated transposases and hypothetical genes and it also exhibits anomalous G+C content.</p><p><i>A. ferrooxidans</i> may also be resistant to some antibiotics due to the presence of a two-gene cluster (AFE1977-78) potentially encoding a fosfomidocyn resistance protein and a TonB-family protein, respectively, and also a gene potentially encoding an AmpG permease protein (AFE1961).</p><h3 class="c-article__sub-heading" id="Sec27">7. Stress responses</h3><p>For aerobically growing bacteria, the autooxidation of oxidases in the respiratory chain is the main source of endogenous reactive oxygen species (ROS). Increased levels of ROS can also result from exposure to redox active metals, including iron. Aerobic biomining microorganisms such as <i>A. ferrooxidans</i> that thrive in iron-rich environments are thus expected to be well equipped to deal with disturbances in oxidant-antiooxidant balance. Surprisingly, an unexpectedly low number of genes encoding known ROS detoxification functions were identified in the genome. These genes include a Mn-superoxide dismutase encoded by <i>sodA</i> (AFE1898), two non-identical copies of <i>ahpC</i>-like (AFE1468, AFE0985) and <i>ahpD</i>-like (AFE02014, AFE1814) members of the alkylhydroperoxidase family, and <i>nox</i>, (AFE1803) potentially encoding a NADH oxidase (FAD-dependent pyridine nucleotide-disulfide oxidoreductase family protein). This latter is considered to be important in oxygen scavenging in anaerobes because of its potential to reduce oxygen to water [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 115" title="Kawasaki S, Ishikura J, Chiba D, Nishino T, Niimura Y: Purification and characterization of an H2O-forming NADH oxidase from Clostridium aminovalericum: existence of an oxygen-detoxifying enzyme in an obligate anaerobic bacteria. Arch Microbiol. 2004, 181: 324-330. 10.1007/s00203-004-0659-3." href="/articles/10.1186/1471-2164-9-597#ref-CR115" id="ref-link-section-d25988610e2535">115</a>]. No genes coding for known catalases were detected.</p><p>On the other hand, <i>A. ferrooxidans</i> is predicted to have a complete set of components needed for non-enzymatic neutralization of ROS. This mechanism maintains high levels of low molecular weight thiols in the cytoplasm that, in combination with specific disulfide reductases, provide a reducing intracellular environment and maintain the thiol/disulfide balance of other molecules (unpublished results). Seven distinct thioredoxins (<i>txr</i>; AFE2867, AFE2848, AFE2590, AFE2362, AFE1979, AFE0657, AFE0047) and one thioredoxin disulfide reductase (<i>trxB</i>, AFE0375) are present. Also present are the genes of the glutathione system necessary for glutathione-tripeptide synthesis from the amino acids L-cysteine, L-glutamate, and glycine (<i>gshA</i>, AFE03064; <i>gshB</i>, AFE03063), four distinct glutaredoxins (<i>gxr</i>; AFE3038, AFE2449, AFE2263, AFE0367), and the glutathione reductase <i>gorA</i> (AFE0366).</p><p>In some bacteria, when basic protection is not sufficient, e.g., when sudden large increases in ROS occur, rapid global responses are induced to cope with the oxidative stress [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 116" title="Zheng M, Doan B, Schneider T, Storz G: OxyR and SoxRS regulation of fur. J Bacteriol. 1999, 181: 4639-4643." href="/articles/10.1186/1471-2164-9-597#ref-CR116" id="ref-link-section-d25988610e2566">116</a>]. Often survival during the period of stress is aided by the simultaneous employment of multiple strategies. The strategies predicted to be available to <i>A. ferrooxidans</i> include repair of oxidative damage (e.g., <i>nfo</i>), bypassing of damaged functions (e.g., resistant isozymes <i>acnA, fumC</i>), and the exclusion of oxidative stress agents (e.g., <i>acrAB</i> multidrug efflux pump). Typically, many of these functions are coordinately regulated in response to superoxide by the SoxRS two-component regulator, and in response to peroxide by OxyR in Gram-negative bacteria or by PerR in Gram-positive bacteria. <i>A. ferrooxidans</i> lacks <i>oxyR</i>, <i>soxR</i>, and <i>soxS</i> orthologs, but has a Fur family regulator similar to PerR (AFE1467). The role of PerR in the control of <i>A. ferrooxidans</i> inducible stress response has not been investigated, but could include regulation of the divergently-transcribed AhpC family peroxidase (AFE1468). This arrangement is conserved in other microorganisms [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 117" title="Zahrt TC, Song J, Siple J, Deretic V: Mycobacterial FurA is a negative regulator of catalase-peroxidase gene katG. Mol Microbiol. 2001, 39 (5): 1174-1185. 10.1111/j.1365-2958.2001.02321.x." href="/articles/10.1186/1471-2164-9-597#ref-CR117" id="ref-link-section-d25988610e2597">117</a>].</p><p>Other antioxidant defenses that are not controlled by the major oxidative stress regulators include the DNA repair enzyme endonuclease III (<i>nth</i>, AFE2682), glycoylases (<i>mutM</i>, AFE2758; <i>mutY</i>, AFE3015), DNA polymerase I (<i>polA</i>, AFE3094), recombinase protein A (<i>recA</i>, AFE0932), and other defenses including a peptide methionine sulfoxide reductase (<i>msrAB</i>, AFE2946-45) and a molecular chaperone (<i>hlsO</i>, AFE1408).</p><h3 class="c-article__sub-heading" id="Sec28">8. Flagella formation and chemotaxis</h3><p>Conserved <i>fla</i> or <i>fla</i>-related genes that could encode flagella were not identified in the genome, nor were <i>che</i> genes that encode classic chemotaxis functions. These observations conflict with Ohmura et al. (1996) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 118" title="Ohmura N, Tsugita K, Koizumi J, Saiki H: Sulfur-binding protein of flagella of Thiobacillus ferrooxidans. J Bacteriol. 1996, 178 (19): 5776-5780." href="/articles/10.1186/1471-2164-9-597#ref-CR118" id="ref-link-section-d25988610e2642">118</a>] who proposed that the formation of flagella was a major factor mediating the adhesion of <i>A. ferrooxidans</i> ATCC 23270 to solid sulfur surfaces. This discrepancy could be explained if the <i>fla</i> genes have been lost in the particular culture used for sequencing. Since flagella genes are encoded in a multigene operon in many bacteria, their complete loss might require only one or a small number of excision events. In contrast, the multiple <i>che</i> genes are usually widely dispersed in bacterial genomes and their collective loss in <i>A. ferrooxidans</i> ATCC 23270 would presumably require multiple excision events. Alternative hypotheses to explain this discrepancy include (i) contamination of the <i>A. ferrooxidans</i> ATCC 23270 culture used by Ohmura et al. (1996) by a flagella-bearing microorganism, and (ii) significant differences between the culture used by Ohmura et al. (1996) and that used for our genome sequencing despite their identical designation (ATCC 23270).</p><h3 class="c-article__sub-heading" id="Sec29">9. Adhesion and biofilm formation</h3><p>For mineral-associated bacteria, adhesion and biofilm formation are critical steps for colonization and subsequent mineral solubilization [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 119" title="Sand W, Gehrke T: Extracellular polymeric substances mediate bioleaching/biocorrosion via interfacial processes involving iron(III) ions and acidophilic bacteria. Res Microbiol. 2006, 157 (1): 49-56. 10.1016/j.resmic.2005.07.012." href="/articles/10.1186/1471-2164-9-597#ref-CR119" id="ref-link-section-d25988610e2669">119</a>]. Cell surface structures such as pili have been shown to play a critical role in auto-aggregation of microbial cells involved in biogeochemical processes [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 120" title="Reguera G, Pollina R, Nicoll J, Lovley D: Possible nonconductive role of Geobacter sulfurreducens pilus nanowires in biofilm formation. J Bacteriol. 2007, 189 (5): 2125-2127. 10.1128/JB.01284-06." href="/articles/10.1186/1471-2164-9-597#ref-CR120" id="ref-link-section-d25988610e2672">120</a>]. <i>A. ferrooxidans</i> contains several gene clusters potentially involved in the formation of a type IV pilus (AFE0967-73, AFE0735-39, AFE0416, AFE0183-6, and AFE0006-7). Some of the relevant genes identified include those for the σ<sub>54</sub>-dependent transcriptional regulator <i>pilR</i> (AFE0185) and for the signal transduction histidine kinase <i>pilS</i> (AFE0184). In addition, candidate <i>tad</i> (tight adherence) genes (AFE2699-AFE2708) were also detected (Additional file <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/10.1186/1471-2164-9-597#MOESM5">5</a>). These genes are responsible for the secretion and assembly of bundled pili. In <i>A. actinomycetemcomitans</i>, they are essential for tight adherence, autoaggregation, and pili formation during colonization of dental surfaces [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 121" title="Schreiner H, Sinatra K, Kaplan J, Furgang D, Kachlany S, Planet P, Perez B, Figurski D, Fine D: Tight-adherence genes of Actinobacillus actinomycetemcomitans are required for virulence in a rat model. Proc Natl Acad Sci USA. 2003, 100 (12): 7295-7300. 10.1073/pnas.1237223100." href="/articles/10.1186/1471-2164-9-597#ref-CR121" id="ref-link-section-d25988610e2696">121</a>]. They are also present in <i>Thiomicrospora crunogena</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 88" title="Scott KM, Sievert SM, Abril FN, Ball LA, Barrett CJ, Blake RA, Boller AJ, Chain PS, Clark JA, Davis CR: The genome of deep-sea vent chemolithoautotroph Thiomicrospira crunogena XCL-2. PLoS Biol. 2006, 4 (12): e383-10.1371/journal.pbio.0040383." href="/articles/10.1186/1471-2164-9-597#ref-CR88" id="ref-link-section-d25988610e2703">88</a>], a RISCs-oxidizing, chemoautotrophic bacterium found in thermal vents. The multiple copies of genes for pili biosynthesis and adhesion in <i>A. ferrooxidans</i> could enable attachment and colonization on various mineral surfaces, such as pyrite, chalcopyrite, and solid sulfur. The redundancy of related regulatory genes could allow <i>A. ferrooxidans</i> to respond successfully to environmental changes.</p><p>Genes involved in quorum sensing that were previously identified and characterized include those that encode the classical autoinducer-binding transcriptional regulator LuxR (AFE1997) and the autoinducer synthesis protein LuxI (AFE1999) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 122" title="Rivas M, Seeger M, Holmes D, Jedlicki E: A Lux-like quorum sensing system in the extreme acidophile Acidithiobacillus ferrooxidans. Biol Res. 2005, 38 (2–3): 283-297." href="/articles/10.1186/1471-2164-9-597#ref-CR122" id="ref-link-section-d25988610e2715">122</a>]. In addition, a second route for the production of homoserine lactones using the act system was predicted based on the presence of a gene encoding an acyltranferase (<i>act</i>, AFE2584) that was shown to be involved in the production of homoserine lactones of C14 length [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 123" title="Rivas M, Seeger M, Jedlicki E, Holmes D: Second acyl homoserine lactone production system in the extreme acidophile Acidithiobacillus ferrooxidans. Appl Environ Microbiol. 2007, 73 (10): 3225-3231. 10.1128/AEM.02948-06." href="/articles/10.1186/1471-2164-9-597#ref-CR123" id="ref-link-section-d25988610e2721">123</a>].</p><p>A five gene operon, containing <i>luxA</i>-<i>galE</i>-<i>galK</i>-<i>pgm</i>-<i>galM</i>, was assigned gene numbers AFE1341-45, respectively. This operon has been proposed to be involved in the formation of extra-cellular polysaccharide (EPS) precursors via the Leloir pathway [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 100" title="Barreto M, Jedlicki E, Holmes DS: Identification of a gene cluster for the formation of extracellular polysaccharide precursors in the chemolithoautotroph Acidithiobacillus ferrooxidans. Appl Environ Microbiol. 2005, 71 (6): 2902-2909. 10.1128/AEM.71.6.2902-2909.2005." href="/articles/10.1186/1471-2164-9-597#ref-CR100" id="ref-link-section-d25988610e2743">100</a>]. <i>GalU</i> (AFE0445) and <i>galT</i>-like (AFE1237) have also been predicted to form part of the Leloir pathway and genes <i>rfbA</i>, <i>B</i>, <i>C</i> and <i>D</i> (AFE3295, AFE0441, AFE3294 and AFE0442, respectively) have been proposed to be involved in the biosynthesis of the EPS precursor dTDP-rhamnose. These groups of genes have been postulated to be involved in biofilm formation in <i>A. ferrooxidans</i> and their patterns of transcription were characterized in growth media with and without organic carbon supplementation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 100" title="Barreto M, Jedlicki E, Holmes DS: Identification of a gene cluster for the formation of extracellular polysaccharide precursors in the chemolithoautotroph Acidithiobacillus ferrooxidans. Appl Environ Microbiol. 2005, 71 (6): 2902-2909. 10.1128/AEM.71.6.2902-2909.2005." href="/articles/10.1186/1471-2164-9-597#ref-CR100" id="ref-link-section-d25988610e2768">100</a>].</p><h3 class="c-article__sub-heading" id="Sec30">10. Genetic transfer</h3><p>A region of the genome (AFE1013-AFE1387, Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-2164-9-597#Fig2">2</a>) is enriched (84% versus 54% for the rest of the genome) in putative genes encoding hypothetical proteins, genes for DNA metabolism and sequences related to mobile elements such as transposases, plasmids, and bacteriophage (phage), and pseudogenes. The presence of site-specific recombinases and phage integrases in this region, as well as in other regions such as AFE2397-99, AFE0833-35 and AFE0507-9, indicates that <i>A. ferrooxidans</i> has been the target of phage infection. Although no phages are currently known to infect <i>A. ferrooxidans</i>, this finding suggests that further searching might be fruitful. Such phage could facilitate study of the mechanisms of viral infection in extremely acidic conditions, as well as serve as useful transducing agents for the genetic manipulation of <i>A. ferrooxidans</i>, as have been shown for the acidophilic archaeon, <i>Sulfolobus</i> spp. [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 124" title="Martin A, Yeats S, Janekovic D, Reiter WD, Aicher W, Zillig W: SAV 1, a temperate u.v.-inducible DNA virus-like particle from the archaebacterium Sulfolobus acidocaldarius isolate B12. Embo J. 1984, 3 (9): 2165-2168." href="/articles/10.1186/1471-2164-9-597#ref-CR124" id="ref-link-section-d25988610e2795">124</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 125" title="Zillig W: Confusion in the assignments of Sulfolobus sequences to Sulfolobus species. Nucleic Acids Res. 1993, 21 (22): 5273-10.1093/nar/21.22.5273." href="/articles/10.1186/1471-2164-9-597#ref-CR125" id="ref-link-section-d25988610e2798">125</a>].</p><p>The genome contains clusters of genes whose sequence and gene order show significant similarity to both the Trb system of the Ri plasmid from <i>Rhizobium rhizogenes</i> and the Ti plasmid from <i>Agrobacterium tumefaciens</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 126" title="Barreto M, Valdes J, Dominguez C, Arriagada C, Silver S, Bueno S, Jedlicki E, Holmes D: Whole Genome Sequence of Acidithiobacillus ferrooxidans: Metabolic Reconstruction, Heavy Metal Resistance and Other Characteristics. Biohydrometallurgy: Fundamentals, Technology and Sustainable Development: 2001. 2001, Minas Gerais, Brazil: Elsevier Press, 237-251." href="/articles/10.1186/1471-2164-9-597#ref-CR126" id="ref-link-section-d25988610e2810">126</a>]. Most of these predicted genes potentially encode structural proteins of the type IV secretion system involved in conjugative DNA transfer. However, missing from the genome are the <i>trbC</i>, <i>trbH</i>, and <i>trbK</i> genes that encode an inner membrane lipoprotein, a pili structural protein, and a protein involved in plasmid immunity, respectively. Notably, one of two copies of a <i>trbG</i>-like gene is located within a highly conserved cluster in a position usually occupied by <i>trbH</i>, and it may assume the role of this missing gene. The absence of critical components of the conjugation system suggests that <i>A. ferrooxidans</i> ATCC 23270 has lost the capacity to carry out conjugation via the Trb mechanism. The question arises as to the origin of the Ti plasmid-like sequences in <i>A. ferrooxidans</i>. One possibility is that it was acquired from an <i>Agrobacterium</i>-related microorganism or an ancestor of such through conjugation. <i>A. ferrooxidans</i> and a free-living or plant root-associated <i>Agrobacterium</i> might share the same environment at the interface of acidic drainages and anaerobic soils/water.</p><p>Ten proteins predicted to be involved in plasmid stability and maintenance are present in the genome. This discovery, coupled with the detection of an extensive suite of predicted conjugation-related genes, provides additional evidence that <i>A. ferrooxidans</i> was capable of undergoing conjugation. Even though no natural conjugation partners are known, conjugation between <i>E. coli</i> and <i>A. ferrooxidans</i> has been achieved in the laboratory. The frequency of detectable marker transfer has been very low [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 95" title="Liu Z, Borne F, Bonnefoy V: Genetic transfer of IncP, IncQ and IncW plasmids to four Thiobacillus ferrooxidans strains by conjugation. Hydrometallurgy. 2001, 59: 339-345. 10.1016/S0304-386X(00)00176-6." href="/articles/10.1186/1471-2164-9-597#ref-CR95" id="ref-link-section-d25988610e2857">95</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 127" title="Liu Z, Guiliani N, Appia-Ayme C, Borne F, Ratouchniak J, Bonnefoy V: Construction and characterization of a recA mutant of Thiobacillus ferrooxidans by marker exchange mutagenesis. J Bacteriol. 2000, 182 (8): 2269-2276. 10.1128/JB.182.8.2269-2276.2000." href="/articles/10.1186/1471-2164-9-597#ref-CR127" id="ref-link-section-d25988610e2860">127</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 128" title="Peng J, Yan W, Bao X: Plasmid and transposon transfer to Thiobacillus ferrooxidans. J Bacteriol. 1994, 176 (10): 2892-2897." href="/articles/10.1186/1471-2164-9-597#ref-CR128" id="ref-link-section-d25988610e2864">128</a>], and must be increased before this technique can be used for widespread genetic manipulation of <i>A. ferrooxidans</i>. Our finding of conjugation-related genes could stimulate further attempts.</p><p>Forty-one IS elements were identified, of which thirty-three could be classified as members of nine families according to the scheme of Mahillon and Chandler [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 129" title="Siguier P, Filee J, Chandler M: Insertion sequences in prokaryotic genomes. Curr Opin Microbiol. 2006, 9 (5): 526-531. 10.1016/j.mib.2006.08.005." href="/articles/10.1186/1471-2164-9-597#ref-CR129" id="ref-link-section-d25988610e2873">129</a>] (Additional file <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/10.1186/1471-2164-9-597#MOESM3">3</a>). The largest groups, designated here as ISafe3 (8 copies) and ISafe4 (3 copies), belong to the IS110 and IS3 families, respectively [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 129" title="Siguier P, Filee J, Chandler M: Insertion sequences in prokaryotic genomes. Curr Opin Microbiol. 2006, 9 (5): 526-531. 10.1016/j.mib.2006.08.005." href="/articles/10.1186/1471-2164-9-597#ref-CR129" id="ref-link-section-d25988610e2879">129</a>]. ISafe1, which is associated with phenotypic switching in <i>A. ferrooxidans</i> ATCC 19859 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 130" title="Holmes DS, Zhao HL, Levican G, Ratouchniak J, Bonnefoy V, Varela P, Jedlicki E: ISAfe1, an ISL3 family insertion sequence from Acidithiobacillus ferrooxidans ATCC 19859. J Bacteriol. 2001, 183 (14): 4323-4329. 10.1128/JB.183.14.4323-4329.2001." href="/articles/10.1186/1471-2164-9-597#ref-CR130" id="ref-link-section-d25988610e2885">130</a>], was not detected in the genome of the type strain. Two non-identical copies of a Tn5468 transposon (family Tn7-like) were detected, each containing <i>tnsABCDorf5</i> (AFE1201-AFE1205, AFE3199-95). The first copy is embedded in a suite of genes encoding hypothetical proteins; the second is associated with the <i>atp</i> operon and the <i>glmSU</i> as described for <i>A. ferrooxidans</i> ATCC 33020 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 131" title="Oppon JC, Sarnovsky RJ, Craig NL, Rawlings DE: Tn7-like transposon is present in the glmUS region of the obligately chemoautolithotrophic bacterium Thiobacillus ferrooxidans A. J Bacteriol. 1998, 180 (11): 3007-3012." href="/articles/10.1186/1471-2164-9-597#ref-CR131" id="ref-link-section-d25988610e2901">131</a>].</p><h3 class="c-article__sub-heading" id="Sec31">11. Predicted osmotic balance and potential pH tolerance mechanisms</h3><p>Acidophiles exhibit functional and structural properties that allow them to survive and proliferate in extremely acidic environments (pH 3 or below) [reviewed in 132]. These include: a) impermeable cell membranes (mostly in archaea); b) selective outer membrane porins; c) the generation of positive internal potential (Δψ) to create a chemosmotic barrier inhibiting proton influx; and d) the removal of excess internal protons by active proton pumping.</p><p>A putative gene (<i>omp40</i>, AFE2741) was identified that had significant similarity to an outer membrane porin found in <i>A. ferrooxidans</i> strain ATCC 19859 (133, 134). A large external, positively-charged loop has been predicted in Omp40 that may control pore size and ion selectivity at the porin entrance and may constitute a potential proton barrier [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 133" title="Amaro AM, Chamorro D, Seeger M, Arredondo R, Peirano I, Jerez CA: Effect of external pH perturbations on in vivo protein synthesis by the acidophilic bacterium Thiobacillus ferrooxidans. J Bacteriol. 1991, 173 (2): 910-915." href="/articles/10.1186/1471-2164-9-597#ref-CR133" id="ref-link-section-d25988610e2921">133</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 134" title="Guiliani N, Jerez CA: Molecular cloning, sequencing, and expression of omp-40, the gene coding for the major outer membrane protein from the acidophilic bacterium Thiobacillus ferrooxidans. Appl Environ Microbiol. 2000, 66 (6): 2318-2324. 10.1128/AEM.66.6.2318-2324.2000." href="/articles/10.1186/1471-2164-9-597#ref-CR134" id="ref-link-section-d25988610e2924">134</a>].</p><p>In addition, the following related functions were predicted (Additional file <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/10.1186/1471-2164-9-597#MOESM3">3</a>): several potassium transporters including one K+ channel, one K+ uptake protein and one K+ efflux transporter; two copies of an ABC potassium import system that could be involved in the generation of a positive internal potential inhibiting proton influx; four Na/H+ antiporters and two proton P-type ATPases that could extrude excess internal protons. These predictions suggest specific areas for future experimental validation.</p></div></div></section><section data-title="Conclusion"><div class="c-article-section" id="Sec32-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec32">Conclusion</h2><div class="c-article-section__content" id="Sec32-content"><p>• Bioinformatics analysis of the complete genome of the type strain of <i>A. ferrooxidans</i> (ATCC 23207) provides a valuable platform for gene discovery and functional prediction that is especially important given the difficulties in carrying out standard genetic research in this microorganism. The models presented herein should facilitate the design and interpretation of future experiments and enable the experimental investigator to focus on important issues.</p><p>• An analysis of the genome of the type strain provides a coherent view of the gene content and metabolic potential of this species (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-2164-9-597#Fig7">7</a>).</p> <div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-7" data-title="Figure 7"><figure><figcaption><b id="Fig7" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 7</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.1186/1471-2164-9-597/figures/7" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig7_HTML.jpg?as=webp"><img aria-describedby="Fig7" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_Article_1790_Fig7_HTML.jpg" alt="figure 7" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-7-desc"><p><b>Whole-cell model</b> <b><i>for A. ferrooxidans</i></b> <b>ATCC 23270</b>. Genome-based model of the cellular metabolism of <i>A. ferrooxidans</i> including predicted transport systems; chemolithoautotrophic components; carbon, nitrogen and sulfur metabolism; and biogeochemical cycling.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.1186/1471-2164-9-597/figures/7" data-track-dest="link:Figure7 Full size image" aria-label="Full size image figure 7" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> <p>• Metabolic models support the key capabilities of <i>A. ferrooxidans</i> that pertain to its use in industrial bioleaching, including its ability to oxidize both sulfur and iron, to resist low pH, and to live in environments with potentially toxic organic and inorganic chemicals. They also suggest that it has the ability to precipitate metals in anaerobic environments, which would be deleterious to copper bioleaching activity.</p><p>• Our analysis also prompts several unexpected predictions, some of which could potentially be useful in biomining such as the proposed connection between biofilm formation and central carbon metabolism and the presence of several predicted quorum sensing mechanisms. Indications of past phage infection and conjugation events suggest potentially fruitful approaches for the development of efficient methods for genetic manipulation of this microorganism.</p><p>• Metabolic models also indicate how this microorganism could play an important role as a producer of fixed carbon and nitrogen and as a recycler of metals in bioleaching operations as well as in natural environments.</p></div></div></section><section data-title="Methods"><div class="c-article-section" id="Sec33-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec33">Methods</h2><div class="c-article-section__content" id="Sec33-content"><h3 class="c-article__sub-heading" id="Sec34">Genome sequencing and assembly</h3><p>The genome was sequenced and assembled using the whole genome shotgun method as previously described [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 135" title="Venter JC, Smith HO, Hood L: A new strategy for genome sequencing. Nature. 1996, 381: 364-366. 10.1038/381364a0." href="/articles/10.1186/1471-2164-9-597#ref-CR135" id="ref-link-section-d25988610e3007">135</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 137" title="Wu M, Sun LV, Vamathevan J, Riegler M, Deboy R, Brownlie JC, McGraw EA, Martin W, Esser C, Ahmadinejad N: Phylogenomics of the reproductive parasite Wolbachia pipientis wMel: a streamlined genome overrun by mobile genetic elements. PLoS Biol. 2004, 2 (3): E69-10.1371/journal.pbio.0020069." href="/articles/10.1186/1471-2164-9-597#ref-CR137" id="ref-link-section-d25988610e3010">137</a>].</p><h3 class="c-article__sub-heading" id="Sec35">Sequence annotation</h3><p>Gene modeling was performed using CRTICA [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 138" title="Badger J, Olsen GJ: CRITICA: coding region identification tool invoking comparative analysis. Mol Biol Evol. 1999, 16 (4): 512-524." href="/articles/10.1186/1471-2164-9-597#ref-CR138" id="ref-link-section-d25988610e3021">138</a>] and GLIMMER [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 139" title="Delcher A, Harmon D, Kasif S, White O, Salzberg SL: Improved microbial gene identification with GLIMMER. Nucleic Acids Res. 1999, 27 (23): 4636-4641. 10.1093/nar/27.23.4636." href="/articles/10.1186/1471-2164-9-597#ref-CR139" id="ref-link-section-d25988610e3024">139</a>]. The lists of open reading frames (ORFs) generated by both strategies were merged using CRITICA start sites when models were identical. The translated ORFs were submitted to BLAST analysis against the UNIPROT database to evaluate overlaps and alternative start sites. The final list of coding sequences (CDSs) was translated, and these amino acid sequences were then used to query the following databases (August-December, 2007): National Center for Biotechnology Information (NCBI) nonredundant database, UniProt, TIGRFam, Pfam, PRIAM, KEGG, COG, and InterPro. Manual functional assignments were performed gene-by-gene, when needed. Comparative genome analyses were also performed using the Comprehensive Microbial Resource [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 140" title="Peterson JD, Umayam LA, Dickinson T, Hickley EK, White O: The Comprehensive Microbial Resource. Nucleic Acids Res. 2001, 29 (1): 123-125. 10.1093/nar/29.1.123." href="/articles/10.1186/1471-2164-9-597#ref-CR140" id="ref-link-section-d25988610e3027">140</a>].</p><h3 class="c-article__sub-heading" id="Sec36">Nucleotide sequence accession numbers</h3><p>The sequence and annotation of the complete <i>A. ferrooxidans</i> strain ATCC 23270 genome is available at the Comprehensive Microbial Resource (CMR) (J. 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Work supported by Fondecyt 1050063, Fondecyt 11060164, DI-UNAB 34-06, DI-UNAB 15-06/I, and a Microsoft Sponsored Research Award. The sequencing and annotation was supported by the U.S. Department of Energy, Office of Biological Energy Research, Cooperative Agreement DE-FC02-95ER61962 to TIGR.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Center for Bioinformatics and Genome Biology, Fundación Ciencia para la Vida and Depto. de Ciencias Biologicas, Facultad de Ciencias de la Salud, Universidad Andres Bello, Santiago, Chile</p><p class="c-article-author-affiliation__authors-list">Jorge Valdés, Inti Pedroso, Raquel Quatrini & David S Holmes</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">J. Craig Venter Institute, Rockville, MD, USA</p><p class="c-article-author-affiliation__authors-list">Robert J Dodson, Herve Tettelin & Jonathan A Eisen</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">The Institute for Genomic Sciences, University of Maryland, Baltimore, MD, USA</p><p class="c-article-author-affiliation__authors-list">Herve Tettelin</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">Section of Evolution and Ecology, U.C. Davis, University of California Davis Genome Center, Davis, CA, USA</p><p class="c-article-author-affiliation__authors-list">Jonathan A Eisen</p></li><li id="Aff5"><p class="c-article-author-affiliation__address">Dept of Medical Microbiology and Immunology, U.C. Davis, University of California Davis Genome Center, Davis, CA, USA</p><p class="c-article-author-affiliation__authors-list">Jonathan A Eisen</p></li><li id="Aff6"><p class="c-article-author-affiliation__address">Division of Basic Pharmaceutical Sciences, Xavier University, New Orleans, LA, USA</p><p class="c-article-author-affiliation__authors-list">Robert Blake II</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Jorge-Vald_s-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Jorge Valdés</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23Jorge%20Vald%C3%A9s" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Jorge%20Vald%C3%A9s" data-track="click" data-track-action="author link - 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A list of genes in the <i>A. ferrooxidans</i> ATCC 23270 genome is provided that are predicted to be involved in amino acid metabolism, cofactor biosynthesis and purine and pyrimidine metabolism. (XLS 81 KB)</p></div></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM2"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="12864_2008_1790_moesm2_esm.png" href="https://static-content.springer.com/esm/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_1790_MOESM2_ESM.png" data-supp-info-image="">12864_2008_1790_MOESM2_ESM.png</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>Additional file 2: <b>Phylogram of four different Rubisco enzymes in various bacteria</b>. Phylogenetic tree of forms I (CbbL1, CbbL2), II (CbbM), and IV (RLP, Rubisco-like protein) of the large subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO) from various organisms. The multiple sequence alignments and trees were produced with ClustalW and visualized with MEGA. Bootstrap values indicated at the nodes are based on 1,000 trials. The RubisCOs from <i>A. ferrooxidans</i> are highlighted by blue boxes. Species names are as follows: <i>Archaeoglobus fulgidus</i>, <i>Bacillus subtilis</i>, <i>Chlorobium limicola</i>, <i>Chlorobium tepidum</i>, <i>Hydrogenovibrio marinus</i>, <i>Ralstonia eutropha</i>, <i>Rhodobacter capsulatus</i>, <i>Rhodobacter sphaeroides</i>, <i>Rhodopseudomonas palustris</i>, <i>Rhodospirilum rubrum</i>, <i>Synechococcus</i> sp. PCC6301, <i>Thiobacillus intermedius</i>, and <i>Thiobacillus neapolitanus</i>. (PNG 153 KB)</p></div></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM3"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="12864_2008_1790_moesm3_esm.pdf" href="https://static-content.springer.com/esm/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_1790_MOESM3_ESM.pdf" data-supp-info-image="">12864_2008_1790_MOESM3_ESM.pdf</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>Additional file 3: <b>Gene lists and predicted properties for several metabolic and cellular processes</b>. This data provides a list of genes and predicted properties for transposase families, hydrogenase systems, nutrient transport systems, osmotic balance, heavy metal resistance systems and toxic organic compounds extrusion systems deduced from the <i>A. ferrooxidans</i> ATCC 23270 genome sequence. (PDF 160 KB)</p></div></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM4"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="12864_2008_1790_moesm4_esm.pdf" href="https://static-content.springer.com/esm/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_1790_MOESM4_ESM.pdf" data-supp-info-image="">12864_2008_1790_MOESM4_ESM.pdf</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>Additional file 4: Gene clusters predicted to be involved in nitrogen metabolism. This data provides a schematic representation of some of the gene clusters and genes predicted to be involved in nitrogen fixation. (PDF 460 KB)</p></div></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM5"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="12864_2008_1790_moesm5_esm.pdf" href="https://static-content.springer.com/esm/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_1790_MOESM5_ESM.pdf" data-supp-info-image="">12864_2008_1790_MOESM5_ESM.pdf</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>Additional file 5: Genes predicted to be involved type IV pilus formation. This data provides a list of genes predicted to be involved type IV pilus formation. (PDF 60 KB)</p></div></div></div></div></div></section><section data-title="Authors’ original submitted files for images"><div class="c-article-section" id="Sec38-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec38">Authors’ original submitted files for images</h2><div class="c-article-section__content" id="Sec38-content"><div data-test="supplementary-info"><p>Below are the links to the authors’ original submitted files for images.</p><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM6"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="authors’ original file for figure 1" href="https://static-content.springer.com/esm/art%3A10.1186%2F1471-2164-9-597/MediaObjects/12864_2008_1790_MOESM6_ESM.jpeg" data-supp-info-image="">Authors’ original file for figure 1</a></h3></div><div 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