{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T01:33:32Z","timestamp":1785202412303,"version":"3.55.0"},"reference-count":72,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T00:00:00Z","timestamp":1708560000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T00:00:00Z","timestamp":1708560000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["Ni262\/19"],"award-info":[{"award-number":["Ni262\/19"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Bacteriol"],"published-print":{"date-parts":[[2024,2,22]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              In\n              <jats:italic>Cupriavidus metallidurans<\/jats:italic>\n              and other bacteria, biosynthesis of the essential biochemical cofactor tetrahydrofolate (THF) initiates from guanosine triphosphate (GTP). This step is catalyzed by FolE_I-type GTP cyclohydrolases, which are either zinc-dependent FolE_IA-type or metal-promiscuous FolE_IB-type enzymes. As THF is also essential for GTP biosynthesis, GTP and THF synthesis form a cooperative cycle, which may be influenced by the cellular homeostasis of zinc and other metal cations. Metal-resistant\n              <jats:italic>C. metallidurans<\/jats:italic>\n              harbors one FolE_IA-type and two FolE_IB-type enzymes. All three proteins were produced in\n              <jats:italic>Escherichia coli<\/jats:italic>\n              . FolE_IA was indeed zinc dependent and the two FolE_IB enzymes metal-promiscuous GTP cyclohydrolases\n              <jats:italic>in vitro<\/jats:italic>\n              , the latter, for example, functioning with iron, manganese, or cobalt. Single and double mutants of\n              <jats:italic>C. metallidurans<\/jats:italic>\n              with deletions in the\n              <jats:italic>folE_I<\/jats:italic>\n              genes were constructed to analyze the contribution of the individual FolE_I-type enzymes under various conditions. FolE_IA was required in the presence of cadmium, hydrogen peroxide, metal chelators, and under general metal starvation conditions. FolE_IB1 was important when zinc uptake was impaired in cells without the zinc importer ZupT (ZIP family) and in the presence of trimethoprim, an inhibitor of THF biosynthesis. FolE_IB2 was needed under conditions of low zinc and cobalt but high magnesium availability. Together, these data demonstrate that\n              <jats:italic>C. metallidurans<\/jats:italic>\n              requires all three enzymes to allow efficient growth under a variety of conditions.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Tetrahydrofolate (THF) is an important cofactor in microbial biochemistry. This \u201cAchilles heel\u201d of metabolism has been exploited by anti-metabolites and antibiotics such as sulfonamide and trimethoprim. Since THF is essential for the synthesis of guanosine triphosphate (GTP) and THF biosynthesis starts from GTP, synthesis of both compounds forms a cooperative cycle. The first step of THF synthesis by GTP cyclohydrolases (FolEs) is metal dependent and catalyzed by zinc- or metal-promiscuous enzymes, so that the cooperative THF and GTP synthesis cycle may be influenced by the homeostasis of several metal cations, especially that of zinc. The metal-resistant bacterium\n              <jats:italic>C. metallidurans<\/jats:italic>\n              needs three FolEs to grow in environments with both high and low zinc and cadmium content. Consequently, bacterial metal homeostasis is required to guarantee THF biosynthesis.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/jb.00395-23","type":"journal-article","created":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T13:01:46Z","timestamp":1705410106000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":9,"title":["Protecting the Achilles heel: three FolE_I-type GTP-cyclohydrolases needed for full growth of metal-resistant\n            <i>Cupriavidus metallidurans<\/i>\n            under a variety of conditions"],"prefix":"10.1128","volume":"206","author":[{"given":"Vladislava","family":"Schulz","sequence":"first","affiliation":[{"name":"Molecular Microbiology, Martin-Luther-University Halle-Wittenberg, Halle\/Saale, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Galea","sequence":"additional","affiliation":[{"name":"Molecular Microbiology, Martin-Luther-University Halle-Wittenberg, Halle\/Saale, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Herzberg","sequence":"additional","affiliation":[{"name":"Department of Analytical Chemistry, Helmholtz Centre for Environmental Research \u2013 UFZ, Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4516-8267","authenticated-orcid":true,"given":"Dietrich H.","family":"Nies","sequence":"additional","affiliation":[{"name":"Molecular Microbiology, Martin-Luther-University Halle-Wittenberg, Halle\/Saale, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1039\/c5mt00320b"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010433"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00052-21"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00192-19"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00372-17"},{"key":"e_1_3_3_7_2","first-page":"403","volume-title":"Bacterial stress responses","author":"Mergeay M","year":"2000","unstructured":"Mergeay M. 2000. 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