Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Acquisition of siderophores in Gram-negative bacteria

Nature Reviews Molecular Cell Biology volume 4, pages 105–116 (2003)Cite this article

Key Points

  • Iron is one of the most important nutrients of bacteria, because of its essential metabolic role. However, iron is scarcely available under physiological conditions; first, because of its propensity to form insoluble complexes, and second, as a result of the existence of numerous iron-binding proteins that the host itself uses to store and transport iron.

  • Bacteria have evolved a wide range of strategies to overcome iron shortage and to ensure sufficient uptake. One of these relies on the synthesis and excretion of siderophores, or small compounds that either bind free iron or sequester it from iron-binding proteins in the bacterial environment.

  • In Gram-negative bacteria, recovery of iron-loaded siderophores involves a sophisticated uptake mechanism. At the outer-membrane level, high-affinity receptors capture siderophores and mediate their translocation into the periplasmic space. This is powered by the Ton complex, which resides in cytoplasmic membrane and is coupled to the proton-motive force. Siderophores are subsequently transported across the periplasm and the cytoplasmic membrane by periplasmic-binding proteins and ATP-dependent membrane transporters.

  • In recent years important advancements have been made in the characterization of the siderophore uptake system, owing to the combination of structural, biophysical, biochemical and genetic approaches. Among these, it is worth noting the determination of the atomic structure of several outer-membrane receptors and the use of spectroscopic techniques to monitor the uptake process in vivo.

  • However, fundamental questions concerning almost every aspect of the uptake process remain unclear and are the subject of continued debate between researchers.

Abstract

The outer membrane of Gram-negative bacteria constitutes a permeability barrier that protects the cell from exterior hazards, but also complicates the uptake of nutrients. In the case of iron, the challenge is even greater, because of the scarcity of this indispensable element in the cell's surroundings. To solve this dilemma, bacteria have evolved sophisticated mechanisms whereby the concerted actions of receptor, transporter and energy-transducing proteins ensure that there is a sufficient supply of iron-containing compounds, such as siderophores.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Representative iron-uptake systems in Gram-negative bacteria.
Figure 2: Biological functions of structurally characterized outer-membrane proteins of Gram-negative bacteria.
Figure 3: The TonB-dependent outer-membrane receptors FhuA and FecA.
Figure 4: Carboxy-terminal domain of the putative energy-transducer protein TonB.
Figure 5: Proposed mechanism of uptake of siderophores and vitamin B12 into Gram-negative bacteria.

Similar content being viewed by others

References

  1. Ratledge, C. & Dover, L. G. Iron metabolism in pathogenic bacteria. Annu. Rev. Microbiol. 54, 881–941 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Crichton, R. R. Inorganic biochemistry of iron metabolism: from molecular mechanisms to clinical consequences (John Wiley & Sons, New York, 2001).

    Google Scholar 

  3. Braun, V. & Killmann, H. Bacterial solutions to the iron-supply problem. Trends Biochem. Sci. 24, 104–109 (1999).

    CAS  PubMed  Google Scholar 

  4. Clarke, T. E., Tari, L. W. & Vogel, H. J. Structural biology of bacterial iron uptake systems. Curr. Top. Med. Chem. 1, 7–30 (2001).

    CAS  PubMed  Google Scholar 

  5. Kadner, R. J. Vitamin B12 transport in Escherichia coli: energy coupling between membranes. Mol. Microbiol. 4, 2027–2033 (1990). This review, together with references 6 and 11 – 14, illustrates the evolution of the field of TonB-dependent transport during the past decade. It describes the various permeation mechanisms that were proposed before the determination of the structure of the outer-membrane receptors.

    CAS  PubMed  Google Scholar 

  6. Postle, K. TonB and the Gram-negative dilemma. Mol. Microbiol. 4, 2019–2025 (1990).

    CAS  PubMed  Google Scholar 

  7. Nikaido, H. in Escherichia coli and Salmonella typhimurium: cellular and molecular biology (ed. Neidhardt, F.) 29–47 (American Society for Microbiology, Washington DC, 1996).

    Google Scholar 

  8. Beveridge, T. J. Structures of Gram-negative cell walls and their derived membrane vesicles. J. Bacteriol. 181, 4725–4733 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Koebnik, R., Locher, K. P. & van Gelder, P. Structure and function of bacterial outer membrane proteins: barrels in a nutshell. Mol. Microbiol. 37, 239–253 (2000).

    CAS  PubMed  Google Scholar 

  10. Bradbeer, C. The proton motive force drives the outer membrane transport of cobalamin in Escherichia coli. J. Bacteriol. 175, 3146–3150 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Postle, K. TonB protein and energy transduction between membranes. J. Bioenerg. Biomembr. 25, 591–601 (1993).

    CAS  PubMed  Google Scholar 

  12. Klebba, P. E., Rutz, J. M., Liu, J. & Murphy, C. K. Mechanisms of TonB-catalyzed iron transport through the enteric bacterial cell envelope. J. Bioenerg. Biomembr. 25, 603–611 (1993).

    CAS  PubMed  Google Scholar 

  13. Braun, V. Energy-coupled transport and signal transduction through the Gram-negative outer membrane via TonB-ExbB-ExbD-dependent receptor proteins. FEMS Microbiol. Rev. 16, 295–307 (1995).

    CAS  PubMed  Google Scholar 

  14. Moeck, G. & Coulton, J. W. TonB-dependent iron acquisition: mechanisms of siderophore-mediated active transport. Mol. Microbiol. 28, 675–681 (1998).

    CAS  PubMed  Google Scholar 

  15. Buchanan, S. K. β-Barrel proteins from bacterial outer membranes: structure, function and refolding. Curr. Opin. Struct. Biol. 9, 455–461 (1999).

    CAS  PubMed  Google Scholar 

  16. Schulz, G. E. β-barrel membrane proteins. Curr. Opin. Struct. Biol. 10, 443–447 (2000).

    CAS  PubMed  Google Scholar 

  17. Postle, K. Close before opening. Science 295, 1658–1659 (2002).

    CAS  PubMed  Google Scholar 

  18. Cowan, S. W. et al. Crystal structures explain functional properties of two E. coli porins. Nature 358, 727–733 (1992).

    CAS  PubMed  Google Scholar 

  19. Schirmer, T., Keller, T. A., Wang, Y. F. & Rosenbusch, J. P. Structural basis for sugar translocation through maltoporin channels at 3.1Å resolution. Science 267, 512–514 (1995).

    CAS  PubMed  Google Scholar 

  20. Klebba, P. E. & Newton, S. M. C. Mechanisms of solute transport through the outer membrane proteins: burning down the house. Curr. Biol. 1, 238–248 (1998).

    CAS  Google Scholar 

  21. Schirmer, T. General and specific porins from bacterial outer membranes. J. Struct. Biol. 121, 101–109 (1998).

    CAS  PubMed  Google Scholar 

  22. Ferguson, A. D., Hofmann, E., Coulton, J. W., Diederichs, K. & Welte, W. Siderophore-mediated iron transport: crystal structure of FhuA with bound lipopolysaccharide. Science 282, 2215–2220 (1998).

    CAS  PubMed  Google Scholar 

  23. Locher, K. P. et al. Transmembrane signalling across the ligand-gated FhuA receptor: crystal structures of free and ferrichrome-bound states reveal allosteric changes. Cell 95, 771–778 (1998). References 22 and 23 reported simultaneously the atomic structures of the ferrichrome receptor and transporter FhuA in the ligand-free and -bound states, revealing for the first time the existence of an additional protein domain that blocked the permeation pathway, and showing its role in signalling.

    Article  CAS  PubMed  Google Scholar 

  24. Buchanan, S. K. et al. Crystal structure of the outer membrane active transporter FepA from Escherichia coli. Nature Struct. Biol. 6, 56–63 (1999). This paper reported the atomic structure of the enterobactin receptor and transporter FepA, verifying the common protein architecture of TonB-dependent receptors.

    CAS  PubMed  Google Scholar 

  25. Ferguson, A. D. et al. Structural basis of gating by the outer membrane transporter FecA. Science 295, 1715–1719 (2002). This paper reported the atomic structure of FecA in the ligand-free and -bound states, revealing allosteric changes in the extracellular domain that seem to correspond to a gating mechanism, in addition to changes that involved the plug domain as reported previously.

    CAS  PubMed  Google Scholar 

  26. Scott, D. C. et al. Exchangeability of N-termini in the ligand-gated porins of Escherichia coli. J. Biol. Chem. 276, 13025–13033 (2001).

    CAS  PubMed  Google Scholar 

  27. Moeck, G., Coulton, J. W. & Postle, K. Cell envelope signalling in Escherichia coli: ligand binding to the ferrichrome-iron receptor FhuA promotes interaction with the energy-transducing protein TonB. J. Biol. Chem. 272, 28391–28397 (1997).

    CAS  PubMed  Google Scholar 

  28. Braun, V. Pumping iron through cell membranes. Science 282, 2202–2203 (1998).

    CAS  PubMed  Google Scholar 

  29. Tuckman, M. & Osburne, M. S. In vivo inhibition of TonB-dependent processes by a TonB box consensus pentapeptide. J. Bacteriol. 174, 320–323 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Moeck, G. et al. Ligand-induced conformational change in the ferrichrome-iron receptor of Escherichia coli. Mol. Microbiol. 22, 459–471 (1996).

    CAS  PubMed  Google Scholar 

  31. Larsen, R. A., Foster-Hartnett, D., McIntosh, M. A. & Postle, K. Regions of Escherichia coli TonB and FepA proteins essential for in vivo physical interactions. J. Bacteriol. 179, 3213–3221 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Cadieux, N., Bradbeer, C. & Kadner, R. J. Sequence changes in the TonB box region of BtuB affect its transport activities and interaction with TonB protein. J. Bacteriol. 182, 5954–5961 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Barnard, T. J., Watson, M. E. & McIntosh, M. A. Mutations in Escherichia coli receptor FepA reveal residues involved in ligand binding and transport. Mol. Microbiol. 41, 527–536 (2001).

    CAS  PubMed  Google Scholar 

  34. Merianos, H. J., Cadieux, N., Lin, C. H., Kadner, R. J. & Cafiso, D. S. Substrate-induced exposure of an energy-coupling motif of a membrane transporter. Nature Struct. Biol. 7, 205–209 (2000).

    CAS  PubMed  Google Scholar 

  35. Coggshall, K. A., Cadieux, N., Piedmont, C., Kadner, R. J. & Cafiso, D. S. Transport-defective mutations alter the conformation of the energy-coupling motif of an outer membrane transporter. Biochemistry 40, 13964–13971 (2001).

    CAS  PubMed  Google Scholar 

  36. Chimento, D. P., Mohanty, A. K., Kadner, R. J. & Wiener, M. C. Expression, purification, characterization and crystallization of the E. coli outer membrane cyanocobalamin transporter BtuB. Biophys. J. 82, 2754A (2002).

    Google Scholar 

  37. Wiener, M. C., Chimento, D. P., Mohanty, A. K. & Kadner, R. J. The crystal structure of the E. coli outer membrane cyanocobalamin transporter BtuB. Biophys. J. 82, 2514A (2002).

    Google Scholar 

  38. Braun, M., Killman, H. & Braun, V. The β-barrel domain of FhuAΔ5-160 is sufficient for TonB-dependent activities of Escherichia coli. Mol. Microbiol. 33, 1037–1049 (1999). This paper, together with references 26 and 40, is concerned with the activity of receptors that either lack the plug domain or contain a non-native homologue, which illustrates the current debate about the functional relevance of this domain.

    CAS  PubMed  Google Scholar 

  39. Bonhivers, M. et al. Stability studies of FhuA, a two-domain outer membrane protein from Escherichia coli. Biochemistry 40, 2606–2613 (2001).

    CAS  PubMed  Google Scholar 

  40. Vakharia, H. & Postle, K. FepA with globular domain deletions lacks activity. J. Bacteriol. 184, 5508–5512 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Liu, J., Rutz, J. M., Klebba, P. E. & Feix, J. B. A site-directed spin-labeling study of ligand–induced conformational change in the ferric enterobactin receptor, FepA. Biochemistry 33, 13274–13283 (1994).

    CAS  PubMed  Google Scholar 

  42. Jiang, X. Q. et al. Ligand-specific opening of a gated-porin channel in the outer membrane of living bacteria. Science 276, 1261–1264 (1997).

    CAS  PubMed  Google Scholar 

  43. Bös, C., Lorenzen, D. & Braun, V. Specific in vivo labeling of cell surface-exposed protein loops: reactive cysteines in the predicted gating loop mark a ferrichrome binding site and a ligand-induced conformational change of the Escherichia coli FhuA protein. J. Bacteriol. 180, 605–613 (1998).

    PubMed  PubMed Central  Google Scholar 

  44. Klug, C. S., Eaton, S. S., Eaton, G. R. & Feix, J. B. Ligand-induced conformational change in the ferric enterobactin receptor FepA as studied by site-directed spin labeling and time-domain ESR. Biochemistry 37, 9016–9023 (1998).

    CAS  PubMed  Google Scholar 

  45. Scott, D. C., Newton, S. M. C. & Klebba, P. E. Surface loop motion in FepA. J. Bacteriol. 184, 4906–4911 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Faraldo-Gómez, J. D., Smith, G. R. & Sansom, M. S. P. Molecular dynamics simulations of the bacterial outer membrane protein FhuA: a study of the ferrichrome-free and bound states. Biophys. J. (in the press).

  47. Karplus, M. & Petsko, G. A. Molecular dynamics simulations in biology. Nature 347, 631–639 (1990).

    CAS  PubMed  Google Scholar 

  48. Hansson, T., Oostenbrink, C. & Van Gunsteren, W. F. Molecular dynamics simulations. Curr. Opin. Struct. Biol. 12, 190–196 (2002).

    CAS  PubMed  Google Scholar 

  49. Karplus, M. & McCammon, J. A. Molecular dynamics simulations of biomolecules. Nature Struct. Biol. 9, 646–652 (2002).

    CAS  PubMed  Google Scholar 

  50. Folschweiller, N. et al. The pyoverdin receptor FpvA, a TonB-dependent receptor involved in iron uptake by Pseudomonas aeruginosa. Mol. Membr. Biol. 17, 123–133 (2000).

    CAS  PubMed  Google Scholar 

  51. Schalk, I. J. et al. Copurification of the FpvA ferric pyoverdin receptor of Pseudomonas aeruginosa with its iron-free ligand: implications for siderophore-mediated iron transport. Biochemistry 38, 9357–9365 (1999).

    CAS  PubMed  Google Scholar 

  52. Schalk, I. J. et al. Iron-free pyoverdin binds to its outer membrane receptor FpvA in Pseudomonas aeruginosa: a new mechanism for membrane iron transport. Mol. Microbiol. 39, 351–360 (2001).

    CAS  PubMed  Google Scholar 

  53. Schalk, I. J., Abdallah, M. A. & Pattus, F. Recycling of pyoverdin on the FpvA receptor after ferric pyoverdin uptake and dissociation in Pseudomonas aeruginosa. Biochemistry 41, 1663–1671 (2002). In the studies reported in references 51 – 53, FRET and radiolabelling techniques were used to characterize the association of the receptor FpvA with the siderophore pyoverdin, as well as to monitor its uptake and recycling into the medium.

    CAS  PubMed  Google Scholar 

  54. Stintzi, A., Barnes, C., Jide, X. & Raymond, K. N. Microbial iron-transport via a siderophore shuttle: a membrane ion transport paradigm. Proc. Natl Acad. Sci. USA 97, 10691–10696 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Braun, V. Avoidance of iron toxicity through regulation of bacterial iron transport. Biol. Chem. 378, 779–786 (1997).

    CAS  PubMed  Google Scholar 

  56. Escolar, L., Pérez-Martín, J. & de Lorenzo, V. Opening the iron box: transcriptional metalloregulation by the Fur protein. J. Bacteriol. 181, 6223–6229 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Braun, V. Surface signalling: novel transcription initiation mechanism starting from the cell surface. Arch. Microbiol. 167 (1997). This review and reference 59 describe the process whereby the transcription of the Fec uptake system is regulated by the presence of ferric citrate at the level of the cell surface.

  58. Angerer, A. & Braun, V. Iron regulates transcription of the Escherichia coli ferric citrate transport genes directly and through the transcription initiation proteins. Arch. Microbiol. 169, 483–490 (1998).

    CAS  PubMed  Google Scholar 

  59. Enz, S., Mahren, S., Stroeher, U. W. & Braun, V. Surface signaling in ferric citrate transport gene induction: interaction of the FecA, FecR and FecI regulatory proteins. J. Bacteriol. 182, 637–646 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Stiefel, A. et al. Control of the ferric citrate transport system of Escherichia coli: mutations in region 2.1 of the FecI extracytoplasmic-function sigma factor suppress mutations in the FecR transmembrane regulatory protein. J. Bacteriol. 183, 162–170 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Kim, I., Stiefel, A., Plantör, A., Angerer, A. & Braun, V. 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 (1997).

    CAS  PubMed  Google Scholar 

  62. Howard, S. P., Herrmann, C., Stratilo, C. W. & Braun, V. In vivo synthesis of the periplasmic domain of TonB inhibits transport through the FecA and FhuA iron siderophore transporters of Escherichia coli. J. Bacteriol. 183, 5885–5895 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Wang, C. & Newton, A. An additional step in the transport of iron defined by the tonb locus of Escherichia coli. J. Biol. Chem. 246, 2147–2151 (1971).

    CAS  PubMed  Google Scholar 

  64. Reynolds, P. R., Mottur, G. P. & Bradbeer, C. Transport of vitamin B12 in Escherichia coli. Some observations on the roles of the gene products of btuc and tonb. J. Biol. Chem. 255, 4313–4319 (1980).

    CAS  PubMed  Google Scholar 

  65. Postle, K. & Skare, J. T. Escherichia coli TonB protein is exported from the cytoplasm without proteolytic cleavage of its amino terminus. J. Biol. Chem. 263, 11000–11007 (1988).

    CAS  PubMed  Google Scholar 

  66. Evans, J. S., Levine, B. A., Trayer, I. P., Dorman, C. J. & Higgins, C. F. Sequence-imposed structural constraints in the TonB protein of Escherichia coli. FEBS Lett. 208, 211–216 (1986).

    CAS  PubMed  Google Scholar 

  67. Brewer, S. et al. Structure and function of X-Pro dipeptide repeats in the TonB proteins of Salmonella typhimurium and Escherichia coli. J. Mol. Biol. 216, 883–895 (1990).

    CAS  PubMed  Google Scholar 

  68. Larsen, R. A., Wood, C. & Postle, K. The conserved proline-rich motif is not essential for energy transduction by Escherichia coli TonB protein. Mol. Microbiol. 10, 943–953 (1993).

    CAS  PubMed  Google Scholar 

  69. Holroyd, C. D. & Bradbeer, C. in Microbiology (ed. Schlessinger, D.) 21–23 (American Society for Microbiology, Washington D. C., 1984).

    Google Scholar 

  70. Larsen, R. A., Thomas, M. G. & Postle, K. Protonmotive force, ExbB and ligand-FepA drive conformational changes in TonB. Mol. Microbiol. 31, 1809–1824 (1999). This paper presents evidence that supports a mechanism whereby TonB cycles between different conformations in response to the proton gradient across the cytoplasmic membrane, and proposes a model of energy transduction to the outer-membrane receptors.

    CAS  PubMed  Google Scholar 

  71. Skare, J. T., Ahmer, B. M. M., Seachord, C. L., Darveau, R. P. & Postle, K. Energy transduction between membranes: TonB, a cytoplasmic membrane protein, can be chemically cross-linked in vivo to the outer membrane receptor FepA. J. Biol. Chem. 268, 16302–16308 (1993).

    CAS  PubMed  Google Scholar 

  72. Larsen, R. A. et al. Identification of TonB homologs in the family Enterobacteriaceae and evidence for conservation of TonB-dependent energy transduction complexes. J. Bacteriol. 178, 1363–1373 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Cadieux, N. & Kadner, R. J. Site-directed disulfide bonding reveals an interaction site between energy-coupling protein TonB and BtuB, the outer membrane cobalamin transporter. Proc. Natl Acad. Sci. USA 96, 10673–10678 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Higgs, P. I. et al. TonB interacts with non-receptor proteins at the outer membrane of Escherichia coli. J. Bacteriol. 184, 1640–1648 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Kampfenkel, K. & Braun, V. Membrane topology of the Escherichia coli ExbD protein. J. Bacteriol. 174, 5485–5487 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Kampfenkel, K. & Braun, V. Topology of the ExbB protein in the cytoplasmic membrane of Escherichia coli. J. Biol. Chem. 268, 6050–6057 (1993).

    CAS  PubMed  Google Scholar 

  77. Higgs, P. I., Myers, P. S. & Postle, K. Interactions in the TonB-dependent energy transduction complex: ExbB and ExbD form homomultimers. J. Bacteriol. 180, 6031–6038 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Higgs, P. I., Larsen, R. A. & Postle, K. Quantification of known components of the Escherichia coli TonB energy transduction system: TonB, ExbB, ExbD and FepA. Mol. Microbiol. 44, 271–281 (2002).

    CAS  PubMed  Google Scholar 

  79. Held, K. G. & Postle, K. ExbB and ExbD do not function independently in TonB-dependent energy transduction. J. Bacteriol. 184, 5170–5173 (2002). References 77 – 79 are concerned with the topological characterization of the energy-transducing complex that is formed by the proteins TonB, ExbB and ExbD.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Karlsson, M., Hannavy, K. & Higgins, C. F. ExbB acts as a chaperone-like protein to stabilize TonB in the cytoplasm. Mol. Microbiol. 8, 389–396 (1993).

    CAS  PubMed  Google Scholar 

  81. Traub, I., Gaisser, S. & Braun, V. Activity domains of the TonB protein. Mol. Microbiol. 8, 409–423 (1993).

    CAS  PubMed  Google Scholar 

  82. Larsen, R. A., Thomas, M. G., Wood, G. E. & Postle, K. Partial suppression of an Escherichia coli TonB transmembrane domain mutation (ΔV17) by a missense mutation in ExbB. Mol. Microbiol. 13, 627–640 (1994).

    CAS  PubMed  Google Scholar 

  83. Braun, V. et al. Energy coupled transport across the outer membrane of Escherichia coli: ExbB binds ExbD and TonB in vitro, and leucine 132 in the periplasmic region and aspartate 25 in the transmembrane region are important for ExbD activity. J. Bacteriol. 178, 2836–2845 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Larsen, R. A. & Postle, K. Conserved residues Ser16 and His20 and their relative positioning are essential for TonB activity, cross-linking of TonB with ExbB and the ability of TonB to respond to proton motive force. J. Biol. Chem. 276, 8111–8117 (2001).

    CAS  PubMed  Google Scholar 

  85. Chang, C., Mooser, A., Plückthun, A. & Wlodawer, A. Crystal structure of the dimeric C-terminal domain of TonB reveals a novel fold. J. Biol. Chem. 276, 27535–27540 (2001). This paper reports the atomic structure of a carboxy-terminal fragment of TonB, revealing an unexpected dimeric form.

    CAS  PubMed  Google Scholar 

  86. Moeck, G. & Letellier, L. Characterization of in vitro interactions between a truncated TonB protein from Escherichia coli and the outer membrane receptors FhuA and FepA. J. Bacteriol. 183, 2755–2764 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Neilands, J. B. Siderophores: structure and function of microbial iron transport compounds. J. Biol. Chem. 270, 26723–26726 (1995).

    CAS  PubMed  Google Scholar 

  88. Pattus, F. & Abdallah, M. A. Siderophores and iron-transport in microorganisms. J. Chin. Chem. Soc. 47, 1–20 (2000).

    CAS  Google Scholar 

  89. Roosenberg, J. M., Lin, Y. M., Lu, Y. & Miller, M. J. Studies and synthesis of siderophores, microbial iron chelators and analogs as potential drug delivery agents. Curr. Med. Chem. 7, 159–197 (2000).

    CAS  PubMed  Google Scholar 

  90. Ferguson, A. D. et al. Crystal structure of the antibiotic albomycin in complex with the outer membrane transporter FhuA. Protein Sci. 9, 956–963 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Ferguson, A. D. et al. Active transport of an antibiotic ryfamycin derivative by the outer membrane protein FhuA. Structure 9, 707–716 (2001).

    CAS  PubMed  Google Scholar 

  92. Braun, V. & Braun, M. Active transport of iron and siderophore antibiotics. Curr. Opin. Microbiol 5, 194–201 (2002).

    CAS  PubMed  Google Scholar 

  93. Clarke, T. E., Braun, V., Winkelmann, G., Tari, L. W. & Vogel, H. J. X-ray crystallographic structures of the Escherichia coli periplasmic binding protein FhuD bound to hydroxamate-type siderophores and the antibiotic albomycin. J. Biol. Chem. 277, 13966–13972 (2002).

    CAS  PubMed  Google Scholar 

  94. Kadner, R. J. in Escherichia coli and Salmonella typhimurium: cellular and molecular biology (ed. Neidhardt, F.) 58–87 (American Society for Microbiology, Washington DC, 1996).

    Google Scholar 

  95. Oliver, D. B. in Escherichia coli and Salmonella typhimurium: cellular and molecular biology (ed. Neidhardt, F.) 88–103 (American Society for Microbiology, Washington DC, 1996).

    Google Scholar 

  96. Park, J. T. in Escherichia coli and Salmonella typhimurium: cellular and molecular biology (ed. Neidhardt, F.) 48–57 (American Society for Microbiology, Washington DC, 1996).

    Google Scholar 

  97. Köster, W. ABC transporter-mediated uptake of iron, siderophores, heme and vitamin B12 . Res. Microbiol. 152, 291–301 (2001).

    PubMed  Google Scholar 

  98. Sprencel, C. et al. Binding of ferric enterobactin by the Escherichia coli periplasmic protein FepB. J. Bacteriol. 182, 5359–5364 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Cadieux, N. et al. Identification of the periplasmic cobalamin-binding protein BtuF of Escherichia coli. J. Bacteriol. 184, 706–717 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Locher, K. P., Lee, A. T. & Rees, D. C. The E. coli BtuCD structure: a framework for ABC transporter architecture and mechanism. Science 296, 1091–1098 (2002).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants by the EPSRC, The British Council and La Caixa Foundation. Our thanks to L. Forrest, F. Pattus and I. Schalk for helpful duscussions.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY10021, USA

    José D. Faraldo-Gómez

  2. Department of Biochemistry, Laboratory of Molecular Biophysics, The Rex Richards Building, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK

    Mark S. P. Sansom

Authors
  1. José D. Faraldo-Gómez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark S. P. Sansom
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José D. Faraldo-Gómez.

Related links

Related links

DATABASES

Entrez

BtuB

ExbB

ExbD

FecA

FecB

FecC

FecD

FecE

FecI

FecR

FepA

FhuA

FpvA

Fur

LamB

Lpp

OmpA

OmpF

TonB

FURTHER INFORMATION

José D. Faraldo-Gómez's home page

Glossary

IRON–SULPHUR PROTEIN

A protein that contains one or more clusters of Fe and S atoms, which have an essential role in a wide range of reduction reactions in biological systems, such as oxidative phosphorylation and photosynthesis.

SUPEROXIDE DISMUTASE

An enzyme that is present in all aerobic organisms. It catalyses the conversion of the highly reactive and destructive superoxide anion radicals, which are generated by the metabolism of the cell, into hydrogen peroxide.

TRANSFERRIN

An iron-binding protein that is commonly found in the physiological fluids (serum, milk, saliva, and so on) of many vertebrates. Transferrin acts as an iron carrier with potent antibacterial properties.

HAEMOPHORE

A relatively small protein that is used by Gram-negative bacteria to capture iron-containing haem from complexes such as haemopexin or haemoglobin, and to shuttle it to TonB-dependent outer-membrane receptors, which mediate further uptake into the periplasmic space.

SIDEROPHORE

A low-molecular-weight compound that is produced by bacteria and other microorganisms to sequester iron from other iron-containing molecules in the medium, for example transferrin in a human host.

PORIN

A channel-forming β-barrel protein that resides in the outer membrane of Gram-negative bacteria and mitochondria, across which small molecules and ions diffuse, driven by electrochemical gradients.

PROTON-MOTIVE FORCE

(PMF). The effective force resulting from the relaxation of gradients in the concentration of hydrogen ions across biological membranes, which typically drives functionally important conformational changes in proteins.

GATING

The opening and closing of some pore-forming membrane proteins, to regulate the passage of substances across the cell membrane.

ABC TRANSPORTER

An ATP-driven membrane pump found in all known organisms, the function of which is to mediate the energy-dependent translocation of substrates ranging from inorganic ions and amino acids, to complex polysaccharides and even proteins.

ELECTRON PARAMAGNETIC RESONANCE

(EPR). A spectroscopic technique that, in combination with site-directed spin labelling (or substitution of amino-acid side chains by a nitroxide group), allows the study of the structural and dynamic properties of proteins, typically by providing information on the accessibility, mobility and relative distances of the spin labels used.

CIRCULAR DICHROISM

(CD). The difference in absorption of left and right circularly polarized light — the shape and magnitude of the CD curve as a function of the wavelength of protein/macromolecule solutions is sensitive to changes in the conformation of these solutes.

CHROMOPHORE

The part of a molecule that is responsible for light absorption over a given range of wavelengths.

FLUORESCENCE RESONANCE ENERGY TRANSFER

(FRET). A spectroscopic technique that allows the study of conformational changes in proteins and protein–ligand complexes by monitoring changes in the relative distances between fluorescent groups, such as tryptophan side chains or extrinsic fluorescent probes.

FENTON REACTION

A chemical reaction that occurs when transition metals such as iron interact with hydrogen peroxide. The reaction produces highly reactive and potentially damaging hydroxyl radicals.

PERIPLASMIC-BINDING PROTEIN

A carrier protein found in the periplasmic space of Gram-negative bacteria and mitochondria, the function of which is to facilitate the translocation of nutrients and other compounds across the periplasm and the peptidoglycan mesh.

SIGMA FACTOR

The subunit of the prokaryotic RNA polymerase that is responsible for the recognition of specific initiation sequences (promoters), which leads to gene transcription.

SPHEROPLAST

A bacterial or plant cell from which most of the cell wall has been removed, usually by enzymatic treatment, but which has not lysed.

PROTONOPHORE

(ionophore). A small hydrophobic compound that associates with inorganic ions and protons, and that is able to diffuse across lipid membranes, thereby reducing or abolishing electrochemical gradients across the membrane.

AMPHIPATHIC

In the context of proteins, a segment that contains both hydrophobic (for example, phenylalanine) and hydrophilic (for example, arginine) amino acids.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Faraldo-Gómez, J., Sansom, M. Acquisition of siderophores in Gram-negative bacteria. Nat Rev Mol Cell Biol 4, 105–116 (2003). https://doi.org/10.1038/nrm1015

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1015

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing