Chemistry:Enterobactin

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Enterobactin (also known as enterochelin) is a high affinity siderophore that acquires iron for microbial systems. It is primarily found in Gram-negative bacteria, such as Escherichia coli and Salmonella typhimurium.[1]

Enterobactin is the strongest siderophore known, binding to the ferric ion (Fe3+) with affinity K = 1052 M−1.[2] This value is substantially larger than even some synthetic metal chelators, such as EDTA (Kf,Fe3+ ~ 1025 M−1).[3] Due to its high affinity, enterobactin is capable of chelating even in environments where the concentration of ferric ion is held very low, such as within living organisms. Pathogenic bacteria can steal iron from other living organisms using this mechanism, even though the concentration of iron is kept extremely low due to the toxicity of free iron.

Structure and biosynthesis

Chorismic acid, an aromatic amino acid precursor, is converted to 2,3-dihydroxybenzoic acid (DHB) by a series of enzymes, EntA, EntB and EntC. An amide linkage of DHB to L-serine is then catalyzed by EntD, EntE, EntF and EntB. Three molecules of the DHB-Ser formed undergo intermolecular cyclization, yielding enterobactin.[4] Although a number of stereoisomers are possible due to the chirality of the serine residues, only the Δ-cis isomer is metabolically active.[3] The first three-dimensional structure of a metal enterobactin complex was determined as the vanadium(IV) complex.[5] Although ferric enterobactin long eluded crystallization, its definitive three-dimensional structure was ultimately obtained using racemic crystallography, in which crystals of a 1:1 mixture of ferric enterobactin and its mirror image (ferric enantioenterobactin) were grown and analyzed by X-ray crystallography.[6]

Synthesis of enterobactin starting from chorismate[7]

Mechanism

Iron deficiency in bacterial cells triggers secretion of enterobactin into the extracellular environment, causing formation of a coordination complex "FeEnt" wherein ferric (3+) iron is chelated to the conjugate base of enterobactin. In Escherichia coli, FepA in the bacterial outer membrane then allows entrance of FeEnt to the bacterial periplasm. FepB,C,D and G all participate in transport of the FeEnt through the inner membrane by means of an ATP-binding cassette transporter.[4]

Due to the extreme iron binding affinity of enterobactin, it is necessary to cleave FeEnt with ferrienterobactin esterase to remove the iron. This degradation yields three 2,3-dihydroxybenzoyl-L-serine units. Reduction of the iron (Fe3+ to Fe2+) occurs in conjunction with this cleavage, but no FeEnt bacterial reductase enzyme has been identified, and the mechanism for this process is still unclear.[8] The reduction potential for Fe3+/Fe2+–enterobactin complex is pH dependent and varies from −0.57 V (vs NHE) at pH 6 to −0.79 V at pH 7.4 to −0.99 at pH values higher than 10.4.[9]

Enterobactin has also been shown to have roles in the host, including mammals. Enterobactin is considered a hallmark for pathogenic infection that is sequestered by mammalian protein lipocalin 2 in an attempt to starve the infectious bacteria for iron.[10][11] In contrast, it has also been shown that supplementation with both Ent and FeEnt can benefit the host directly and promote iron uptake in C. elegans and mammalian cultured cells.[12][13][14][15]

History

Enterobactin was discovered by Gibson and Neilands groups in 1970.[16][17] These initial studies established the structure and its relationship to 2,3-dihydroxybenzoic acid.

References

  1. ↑ "Bacillibactin-mediated iron transport in Bacillus subtilis". Journal of the American Chemical Society 128 (1): 22–3. January 2006. doi:10.1021/ja055898c. PMID 16390102. Bibcode: 2006JAChS.128...22D. 
  2. ↑ Carrano, Carl J.; Raymond, Kenneth N. (1979). "Ferric Ion Sequestering Agents. 2. Kinetics and Mechanism of Iron Removal From Transferrin by Enterobactin and Synthetic Tricatechols". J. Am. Chem. Soc. 101 (18): 5401–5404. doi:10.1021/ja00512a047. Bibcode: 1979JAChS.101.5401C. 
  3. ↑ 3.0 3.1 Walsh, Christopher T.; Liu, Jun; Rusnak, Frank; Sakaitani, Masahiro (1990). "Molecular Studies on Enzymes in Chorismate Metabolism and the Enterobactin Biosynthetic Pathway". Chemical Reviews 90 (7): 1105–1129. doi:10.1021/cr00105a003. 
  4. ↑ 4.0 4.1 "Enterobactin: an archetype for microbial iron transport". Proceedings of the National Academy of Sciences of the United States of America 100 (7): 3584–8. April 2003. doi:10.1073/pnas.0630018100. PMID 12655062. 
  5. ↑ Karpishin, Timothy B.; Raymond, Kenneth N. (1992). "The First Structural Characterization of A Metal-Enterobactin Complex: [V(enterobactin)]2-". Angewandte Chemie International Edition in English 31 (4): 466–468. doi:10.1002/anie.199204661. 
  6. ↑ "Determination of the Molecular Structures of Ferric Enterobactin and Ferric Enantioenterobactin Using Racemic Crystallography". Journal of the American Chemical Society 139 (42): 15245–15250. October 2017. doi:10.1021/jacs.7b09375. PMID 28956921. Bibcode: 2017JAChS.13915245J. 
  7. ↑ Raines, D. J.; Sanderson, T. J.; Wilde, E. J.; Duhme-Klair, A. -K. (2015-01-01), "Siderophores", Reference Module in Chemistry, Molecular Sciences and Chemical Engineering (Elsevier), ISBN 978-0-12-409547-2, https://www.sciencedirect.com/science/article/pii/B9780124095472110406, retrieved 2024-07-06 
  8. ↑ "An Iron-Based Molecular Redox Switch as a Model for Iron Release from Enterobactin via the Salicylate Binding Mode". Inorganic Chemistry 38 (22): 5007–5017. November 1999. doi:10.1021/ic990225e. PMID 11671244. 
  9. ↑ Lee, Chi Woo; Ecker, David J.; Raymond, Kenneth N. (1985). "Coordination chemistry of microbial iron transport compounds. 34. The pH-dependent reduction of ferric enterobactin probed by electrochemical methods and its implications for microbial iron transport". J. Am. Chem. Soc. 107 (24): 6920–6923. doi:10.1021/ja00310a030. Bibcode: 1985JAChS.107.6920L. 
  10. ↑ Bird, Lucy (December 2004). "The fight for iron" (in en). Nature Reviews Immunology 4 (12): 930. doi:10.1038/nri1513. ISSN 1474-1741. https://www.nature.com/articles/nri1513. 
  11. ↑ Flo, Trude H.; Smith, Kelly D.; Sato, Shintaro; Rodriguez, David J.; Holmes, Margaret A.; Strong, Roland K.; Akira, Shizuo; Aderem, Alan (December 2004). "Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron" (in en). Nature 432 (7019): 917–921. doi:10.1038/nature03104. ISSN 1476-4687. PMID 15531878. Bibcode: 2004Natur.432..917F. https://www.nature.com/articles/nature03104. 
  12. ↑ Qi, Bin; Han, Min (2018-10-04). "Microbial Siderophore Enterobactin Promotes Mitochondrial Iron Uptake and Development of the Host via Interaction with ATP Synthase". Cell 175 (2): 571–582.e11. doi:10.1016/j.cell.2018.07.032. ISSN 0092-8674. PMID 30146159. https://www.sciencedirect.com/science/article/pii/S0092867418309590. 
  13. ↑ Kim, Dennis H. (2018-10-04). "Bacterial Siderophores Promote Animal Host Iron Acquisition and Growth". Cell 175 (2): 311–312. doi:10.1016/j.cell.2018.09.020. ISSN 0092-8674. PMID 30290138. 
  14. ↑ Anderson, Gregory J. (2018-11-22). "Iron Wars — The Host Strikes Back". New England Journal of Medicine 379 (21): 2078–2080. doi:10.1056/NEJMcibr1811314. ISSN 0028-4793. PMID 30462940. https://www.nejm.org/doi/full/10.1056/NEJMcibr1811314. 
  15. ↑ Sewell, Aileen K.; Cui, Mingxue; Zhu, Mengnan; Host, Miranda R.; Han, Min (2025-02-01). "Enterobactin carries iron into Caenorhabditis elegans and mammalian intestinal cells by a mechanism independent of divalent metal transporter DMT1". Journal of Biological Chemistry 301 (2). doi:10.1016/j.jbc.2025.108158. ISSN 0021-9258. PMID 39761858. Bibcode: 2025JBiCh.301j8158S. 
  16. ↑ "Enterobactin, an iron transport compound from Salmonella typhimurium". Biochemical and Biophysical Research Communications 38 (5): 989–92. March 1970. doi:10.1016/0006-291X(70)90819-3. PMID 4908541. Bibcode: 1970BBRC...38..989P. 
  17. ↑ "Biologically active compounds containing 2,3-dihydroxybenzoic acid and serine formed by Escherichia coli". Biochimica et Biophysica Acta (BBA) - General Subjects 201 (3): 453–60. March 1970. doi:10.1016/0304-4165(70)90165-0. PMID 4908639. 



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