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Regulation of iron uptake minimizes iron-mediated oxidative stress

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Abstract

Sequential accommodation of single electrons by the unpaired orbitals of dioxygen yields oxygen radicals

, hydrogen peroxide (H2O2), hydroxide radicals (OH·), and finally water (H2O). Fe2+ catalyses the formation of the most reactive hydroxide radical from hydrogen peroxide and thus contributes substantially to the toxicity of oxygen. Insolubility of Fe3+ demands the incorporation of iron into transferrin, lactoferrin, ferritin, iron-sulphur clusters, and heme. Bacteria and fungi synthesize low molecular weight compounds, termed siderophores, which are secreted and used to transport Fe3+ into the microbial cells. Iron is economically used and iron toxicity is minimized by the synthesis of siderophores and ferric siderophore transport systems, and by induction of transport gene transcription by certain Fe3+-loaded siderophores. When cells contain sufficient iron, Fe2+-loaded Fur protein and Fe2+-loaded DtxR protein repress gene transcription in Gram-negative bacteria and in most Gram-positive bacteria, respectively. In a recently discovered novel transcription control mechanism, ferric citrate and ferric pseudobactins induce transcription of the iron transport systems by binding to cell surface receptor proteins without entering the cells. Cytoplasmic sigma factors are activated by a signaling device that involves a protein in the outer membrane and a protein in the cytoplasmic membrane. Both proteins extend into the periplasm to transduce the signal through the space between the two membranes. Intracellular iron homeostasis secured by regulation of iron uptake prevents excessive oxidative stress, which could otherwise overcome the cellular defence and repair systems and kill the cells.

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References

  • Angerer A, Enz S, Ochs M and Braun V 1995 Transcription regulation of ferric citrate transport inEscherichia coli K-12. FecI belongs to a new subfamily ofσ 70-type factors that respond to extracytoplasmic stimuli;Mol. Microbiol. 18 163–174

    Article  CAS  Google Scholar 

  • Angerer A M, Gaisser S and Braun V 1990 Nucleotide sequence of thesfuA, sfuB, andsfuC genes ofSerratia marcescens suggest a periplasmic binding protein-dependent iron transport system;J. Bacteriol. 172 572–578

    Article  CAS  Google Scholar 

  • Beckman K B and Ames B N 1997 Oxidative decay of DNA;J. Biol. Chem. 272 19633–19636

    Article  CAS  Google Scholar 

  • Bishop L, Agbayani R, Ambudkar S V, Maloney P C and Ferro-Luzzi Ames G 1989 Reconstitution of a bacterial periplasmic permease in proteoliposomes and demonstration of ATP hydrolysis concomitant with transport;Proc. Natl. Acad. Sci. USA 86 6953–6957

    Article  CAS  Google Scholar 

  • Braun V 1997 Surface signaling: a novel transcription initiation mechanism starting from the cell surface;Arch. Microbiol. 167 325–331

    Article  CAS  Google Scholar 

  • Braun V and Hantke K 1997 Receptor-mediated bacterial iron transport; inTransition metals in microbial metabolism (eds) G Winkelmann and C J Carrano (Amsterdam: Harwood Academic Publishers) pp 81–116

    Google Scholar 

  • Crosa J E 1997 Signal transduction and transcriptional and posttranscriptional control of iron-regulated genes in bacteria;Microbiol. Mol. Biol. Rev. 61 319–336

    CAS  PubMed  PubMed Central  Google Scholar 

  • Davidson A L, Shuman H A and Nikaido H 1992 Mechanism of maltose transport inEscherichia coli: transmembrane signaling by periplasmic binding proteins;Proc. Natl. Acad. Sci. USA 89 2360–2364

    Article  CAS  Google Scholar 

  • Dean C R and Poole K 1993 Expression of the ferric enterobactin receptor (PfeA) ofPseudomonas aeruginosa: involvement of a two-component regulatory system;Mol. Microbiol. 8 1095–1103

    Article  CAS  Google Scholar 

  • Drechsel H and Winkelmann G 1997 Iron chelation and siderophores; inTransition metals in microbial metabolism (eds) G Winkelmann and C J Carrano (Amsterdam: Harwood Academic Publishers) pp 1–49

    Google Scholar 

  • Earhart C F 1996 Uptake and metabolism of iron and molybdenum; inEscherichia coli andSalmonella (ed.) FC Neidhardt (Washington: ASM Press) pp 1075–1090

    Google Scholar 

  • Enz S, Braun V and Crosa J H 1995 Transcription of the region encoding the ferric dicitrate-transport system inEscherichia coli: similarity between promoters forfecA and for extracytoplasmic function sigma factors;Gene 163 13–18

    Article  CAS  Google Scholar 

  • Fath M J and Kolter R 1993 ABC transporters: bacterial exporters;Microbiol. Rev. 57 995–1017

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gaudu P, Moon N and Weiss B 1997 Regulation of thesoxRS oxidative stress regulon. Reversible oxidation of the Fe−S centers of SoxRin vivo;J. Biol. Chem. 272 5082–5086

    Article  CAS  Google Scholar 

  • Genco C A and Desai P J 1996 Iron acquisition in the pathogenicNeisseria;Trends Microbiol. 4 179–184

    Article  CAS  Google Scholar 

  • Ghigo J-M, Letoffe S and Wandersman C 1997 A new type of hemophore-dependent heme acquisition system ofSerratia marcescens reconstituted inEscherichia coli;J. Bacteriol. 179 3572–3579

    Article  CAS  Google Scholar 

  • Gray-Owen S D and Schryvers A B 1996 Bacterial transferrin and lactoferrin receptors;Trends Microbiol 4 185–191

    Article  CAS  Google Scholar 

  • Günter K and Braun V 1990In vivo evidence for FhuA outer membrane receptor interaction with the TonB inner membrane protein ofEscherichia coli;FEBS Lett. 274 85–88

    Article  Google Scholar 

  • Hantke K 1997 Ferrous iron transport by a magnesium transport system is toxic forEscherichia coli andSalmonella typhimurium;J. Bacteriol. 179 6201–6204

    Article  CAS  Google Scholar 

  • Härle C, Kim I, Angerer A and Braun V 1995 Signal transfer through three compartments: transcription initiation of theEscherichia coli ferric citrate transport system from the cell surface;EMBO J. 14 1430–1438

    Article  Google Scholar 

  • Heinrichs D E and Poole K 1993 Cloning and sequence analysis of a gene (pchR) encoding an AraC family activator of pyochelin and ferripyochelin receptor synthesis inPseudomonas aeruginosa;J. Bacteriol. 175 5882–5889

    Article  CAS  Google Scholar 

  • Henle E S and Linn S 1997 Formation, prevention, and repair of DNA damage by iron/hydrogen peroxide;J. Biol. Chem. 272 19095–19089

    Article  CAS  Google Scholar 

  • Hidalgo E, Ding H and Demple B 1997 Redox dignal transduction via iron-sulfur clusters in the SoxR transcription activator;Trends Biochem. Sci. 22 207–210

    Article  CAS  Google Scholar 

  • Jiang X, Payne M A, Cao Z, Foster S B, Feix J B, Newton S M C and Klebba P E 1997 Ligand-specific opening of a gated-porin channel in the outer membrane of living bacteria;Science 276 1261–1264

    Article  CAS  Google Scholar 

  • Kammler M, Schön C and Hantke K 1993 Characterization of the ferrous iron uptake system ofEscherichia coli.J. Bacteriol. 175 6212–6219

    Article  CAS  Google Scholar 

  • Killmann H, Benz R and Braun V 1993 Conversion of the FhuA transport protein into a diffusion channel through the outer membrane ofEscherichia coli;EMBO J. 12 3007–3016

    Article  CAS  Google Scholar 

  • Kim I, Stiefel A, Plantör S, Angerer A and Braun V 1997 Transcription induction of the ferric citrate transport genes via the N-terminus of the FecA outer membrane protein, the Ton system and the electrochemical potential of the cytoplasmic membrane;Mol. Microbiol. 23 333–344

    Article  CAS  Google Scholar 

  • Koster M, van Klompenburg W, Bitter W and Weisbeek P 1994 Role for the outer membrane ferric-siderophore receptor PupB in signal transduction across the bacterial cell envelope;EMBO J. 13 2805–2813

    Article  CAS  Google Scholar 

  • Köster W and Braun V 1990 Iron(III)hydroxamate transport intoEscherichia coli. Substrate binding to the periplasmic FhuD protein;J. Biol. Chem. 265 21407–21410

    PubMed  Google Scholar 

  • Köster W and Böhm B 1992 Point mutations in 2 conserved glycine residues within the integral membrane protein FhuB affect iron(III)hydroxamate transport;Mol. Gen. Genet. 232 399–407

    Article  Google Scholar 

  • Lazazzera B A, Beinert H, Koroshilova N, Kennedy M C and Liley P J 1996 DNA binding and dimerization of the Fe−S-containing FNR protein fromEscherichia coli are regulated by oxygen;J. Biol. Chem. 271 2762–2768

    Article  CAS  Google Scholar 

  • Lonetto M, Brown K L, Rudd K and Buttner M J 1994 Analysis of theStreptomyces coelicolor sigE gene reveals a new sub-family of eubacterial RNA polymerase factors involved in the regulation of extracytoplasmic functions;Proc. Natl. Acad. Sci. USA 91 7573–7577

    Article  CAS  Google Scholar 

  • Lynch A S and Lin E C C 1996 Responses to molecular oxygen; inEscherichia coli andSalmonella (ed.) FC Neidhardt (Washington: ASM Press) pp 1526–1538

    Google Scholar 

  • Mademidis A, Killmann H, Kraas W, Flechsler I, Jung G and Braun V 1997 ATP-dependent ferric hydroxamate transport system inEscherichia coli: periplasmic FhuD interacts with a periplasmic and with a transmembrane/cytoplasmic region of the integral membrane protein FhuB, as revealed by competitive peptide mapping;Mol. Microbiol. 26 1109–1123

    Article  CAS  Google Scholar 

  • Martinez A and Kolter R 1997 Protection of DNA during oxidative stress by the nonspecific DNA-binding protein Dps;J. Bacteriol. 179 5188–5194

    Article  CAS  Google Scholar 

  • Melville S B and Gunsalus R P 1996 Isolation of an oxygen-sensitive FNR protein ofEscherichia coli: interaction at activator and repressor sites of FNR-controlled genes;Proc. Natl. Acad. Sci. USA 93 1226–1231

    Article  CAS  Google Scholar 

  • Moeck G S, Coulton J W and Postle K 1997 Cell envelope signaling inEscherichia coli. Ligand binding to the ferrichrome-iron receptor FhuA promotes interaction with the energy-transducing protein TonB;J. Biol. Chem. 272 28391–28397

    Article  CAS  Google Scholar 

  • Ochs M, Angerer A, Enz S and Braun V 1996 Surface signaling in transcription regulation of the ferric citrate transport system ofEscherichia coli: mutational analysis of the alternative sigma factor FecI supports its essential role infec transport gene transcription;Mol. Gen. Genet. 250 455–465

    CAS  PubMed  Google Scholar 

  • Paraskeva E and Hentze M W 1996 Iron-sulphur clusters a genetic regulatory switches: the bifunctional iron regulatory protein-1;FEBS Lett. 389 40–43

    Article  CAS  Google Scholar 

  • Rohrbach M R, Braun V and Köster W 1995 Ferrichrome transport inEscherichia coli K-12: altered substrate specificity of mutated periplasmic FhuD and interaction of FhuD with the integral membrane protein FhuB;J. Bacteriol. 177 7186–7193

    Article  CAS  Google Scholar 

  • Roualt T A and Klausner R D 1996 Iron-sulfur clusters as biosensors of oxidants and iron;Trends Biochem. Sci. 21 174–177

    Article  Google Scholar 

  • Schneider R and Hantke K 1993 Iron-hydroxamate uptake systems inBacillus subtilis: identification of a lipoprotein as part of a binding protein-dependent transport system;Mol. Microbiol. 8 111–121

    Article  CAS  Google Scholar 

  • Schöffler H and Braun V 1989 Transport across the outer membrane ofEscherichia coli K12 via the FhuA receptor is regulated by the TonB protein in the cytoplasmic membrane;Mol. Gen. Genet. 217 378–383

    Article  Google Scholar 

  • Schultz-Hauser G, Köster W, Schwarz H and Braun V 1992 Iron(III) hydroxamate transport inEscherichia coli K-12: FhuB-mediated membrane association of the FhuC protein and negative complementation offhuC mutants;J. Bacteriol. 174 2305–2311

    Article  CAS  Google Scholar 

  • Smith M A, Harris P L, Sayre L M and Perry G 1997 Iron accumulation in Alzheimer disease is a source of redox-generated free radicals;Proc. Natl. Acad. Sci. USA 94 9866–9868

    Article  CAS  Google Scholar 

  • Stojiljkovic I and Hantke K 1994 Transport of haemin across the cytoplasmic membrane through a haemin-specific periplasmic-binding-protein-dependent transport system inYersinia enterocolitica;Mol. Microbiol. 13 719–832

    Article  CAS  Google Scholar 

  • Stojiljkovic I, Bäumler A and Hantke K 1995 Fur regulon in gram-negative bacteria, identification and characterization of new iron regulatedEscherichia coli genes by a Fur titration assay;J. Mol. Biol. 236 531–545

    Article  Google Scholar 

  • Touati D, Jacques M, Tarda B, Bouchard L and Despied S 1995 Lethal oxidative damage and mutagenesis are generated by iron in Δfur mutants ofEscherichia coli: protective role of superoxide dismutase;J. Bacteriol. 177 2305–2314

    Article  CAS  Google Scholar 

  • Unden G, Becker S, Bongaerts J, Holighaus G, Schirawski J and Six S 1995 O2-sensing and O2-dependent gene regulation in facultatively anaerobic bacteria;Arch. Microbiol. 164 81–90

    CAS  PubMed  Google Scholar 

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Braun, V. Regulation of iron uptake minimizes iron-mediated oxidative stress. J. Biosci. 23, 483–489 (1998). https://doi.org/10.1007/BF02936142

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