Enterobactin
{{chembox
| verifiedrevid = 443726649
| ImageFile=Enterobactin.svg
| ImageSize=250
| PIN=N,N′,N′′-[(3S,7S,11S)-2,6,10-Trioxo-1,5,9-trioxacyclododecane-3,7,11-triyl]tris(2,3-dihydroxybenzamide)
| OtherNames=
|Section1={{Chembox Identifiers
| InChI = 1/C30H27N3O15/c34-19-7-1-4-13(22(19)37)25(40)31-16-10-46-29(44)18(33-27(42)15-6-3-9-21(36)24(15)39)12-48-30(45)17(11-47-28(16)43)32-26(41)14-5-2-8-20(35)23(14)38/h1-9,16-18,34-39H,10-12H2,(H,31,40)(H,32,41)(H,33,42)/t16-,17-,18-/m0/s1
| InChIKey = SERBHKJMVBATSJ-BZSNNMDCBT
| SMILES1 = c1cc(c(c(c1)O)O)C(=O)N[C@H]2COC(=O)[C@H](COC(=O)[C@H](COC2=O)NC(=O)c3cccc(c3O)O)NC(=O)c4cccc(c4O)O
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 432995
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C30H27N3O15/c34-19-7-1-4-13(22(19)37)25(40)31-16-10-46-29(44)18(33-27(42)15-6-3-9-21(36)24(15)39)12-48-30(45)17(11-47-28(16)43)32-26(41)14-5-2-8-20(35)23(14)38/h1-9,16-18,34-39H,10-12H2,(H,31,40)(H,32,41)(H,33,42)/t16-,17-,18-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = SERBHKJMVBATSJ-BZSNNMDCSA-N
| CASNo_Ref = {{cascite|correct|??}}
| CASNo=28384-96-5
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 35C9R2N24F
| PubChem=34231
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 31543
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 28855
| SMILES=C1C(C(=O)OCC(C(=O)OCC(C(=O)O1)NC(=O)C2=C(C(=CC=C2)O)O)NC(=O)C3=C(C(=CC=C3)O)O)NC(=O)C4=C(C(=CC=C4)O)O
}}
|Section2={{Chembox Properties
| Formula=C30H27N3O15
| MolarMass=669.55 g/mol
| Appearance=
| Density=
| MeltingPt=
| BoilingPt=
| Solubility=
}}
|Section3={{Chembox Hazards
| MainHazards=
| FlashPt=
| AutoignitionPt =
}}
}}
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.{{cite journal | vauthors = Dertz EA, Xu J, Stintzi A, Raymond KN | title = Bacillibactin-mediated iron transport in Bacillus subtilis | journal = Journal of the American Chemical Society | volume = 128 | issue = 1 | pages = 22–3 | date = January 2006 | pmid = 16390102 | doi = 10.1021/ja055898c }}
Enterobactin is the strongest siderophore known, binding to the ferric ion (Fe3+) with affinity K = 1052 M−1. This value is substantially larger than even some synthetic metal chelators, such as EDTA (Kf,Fe3+ ~ 1025 M−1). 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. Although a number of stereoisomers are possible due to the chirality of the serine residues, only the Δ-cis isomer is metabolically active. The first three-dimensional structure of a metal enterobactin complex was determined as the vanadium(IV) complex. 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.{{cite journal | vauthors = Johnstone TC, Nolan EM | title = Determination of the Molecular Structures of Ferric Enterobactin and Ferric Enantioenterobactin Using Racemic Crystallography | journal = Journal of the American Chemical Society | volume = 139 | issue = 42 | pages = 15245–15250 | date = October 2017 | pmid = 28956921 | pmc = 5748154 | doi = 10.1021/jacs.7b09375 }}
File:Enterobactin synthesis.svg{{Citation |last=Raines |first=D. J. |title=Siderophores |date=2015-01-01 |work=Reference Module in Chemistry, Molecular Sciences and Chemical Engineering |url=https://www.sciencedirect.com/science/article/pii/B9780124095472110406 |access-date=2024-07-06 |publisher=Elsevier |isbn=978-0-12-409547-2 |last2=Sanderson |first2=T. J. |last3=Wilde |first3=E. J. |last4=Duhme-Klair |first4=A. -K.}}]]
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.
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. 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.
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.{{Cite journal |last=Bird |first=Lucy |date=December 2004 |title=The fight for iron |url=https://www.nature.com/articles/nri1513 |journal=Nature Reviews Immunology |language=en |volume=4 |issue=12 |pages=930–930 |doi=10.1038/nri1513 |issn=1474-1741}}{{Cite journal |last=Flo |first=Trude H. |last2=Smith |first2=Kelly D. |last3=Sato |first3=Shintaro |last4=Rodriguez |first4=David J. |last5=Holmes |first5=Margaret A. |last6=Strong |first6=Roland K. |last7=Akira |first7=Shizuo |last8=Aderem |first8=Alan |date=December 2004 |title=Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron |url=https://www.nature.com/articles/nature03104 |journal=Nature |language=en |volume=432 |issue=7019 |pages=917–921 |doi=10.1038/nature03104 |issn=1476-4687}} 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.{{Cite journal |last=Qi |first=Bin |last2=Han |first2=Min |date=2018-10-04 |title=Microbial Siderophore Enterobactin Promotes Mitochondrial Iron Uptake and Development of the Host via Interaction with ATP Synthase |url=https://www.sciencedirect.com/science/article/pii/S0092867418309590 |journal=Cell |volume=175 |issue=2 |pages=571–582.e11 |doi=10.1016/j.cell.2018.07.032 |issn=0092-8674}}{{Cite journal |last=Kim |first=Dennis H. |date=2018-10-04 |title=Bacterial Siderophores Promote Animal Host Iron Acquisition and Growth |url=https://www.sciencedirect.com/science/article/pii/S0092867418312327 |journal=Cell |volume=175 |issue=2 |pages=311–312 |doi=10.1016/j.cell.2018.09.020 |issn=0092-8674}}{{Cite journal |last=Anderson |first=Gregory J. |date=2018-11-22 |title=Iron Wars — The Host Strikes Back |url=https://www.nejm.org/doi/full/10.1056/NEJMcibr1811314 |journal=New England Journal of Medicine |volume=379 |issue=21 |pages=2078–2080 |doi=10.1056/NEJMcibr1811314 |issn=0028-4793}}{{Cite journal |last=Sewell |first=Aileen K. |last2=Cui |first2=Mingxue |last3=Zhu |first3=Mengnan |last4=Host |first4=Miranda R. |last5=Han |first5=Min |date=2025-02-01 |title=Enterobactin carries iron into Caenorhabditis elegans and mammalian intestinal cells by a mechanism independent of divalent metal transporter DMT1 |url=https://www.sciencedirect.com/science/article/pii/S0021925825000055 |journal=Journal of Biological Chemistry |volume=301 |issue=2 |pages=108158 |doi=10.1016/j.jbc.2025.108158 |issn=0021-9258}}
History
References
{{reflist|refs=
{{cite journal | last1 = Carrano | first1 = Carl J. | first2 = Kenneth N. | last2 = Raymond | name-list-style = vanc | title = Ferric Ion Sequestering Agents. 2. Kinetics and Mechanism of Iron Removal From Transferrin by Enterobactin and Synthetic Tricatechols | journal = J. Am. Chem. Soc. | volume = 101 | year = 1979 | pages = 5401–5404 | doi = 10.1021/ja00512a047 | issue = 18}}
{{cite journal | last1 = Walsh | first1 = Christopher T. | first2 = Jun | last2 = Liu | first3 = Frank | last3 = Rusnak | first4 = Masahiro | last4 = Sakaitani | name-list-style = vanc | title = Molecular Studies on Enzymes in Chorismate Metabolism and the Enterobactin Biosynthetic Pathway | journal = Chemical Reviews | volume = 90 | year = 1990 | pages = 1105–1129 | doi = 10.1021/cr00105a003 | issue = 7}}
{{cite journal | last1 = Karpishin | first1 = Timothy B. | last2 = Raymond | first2 = Kenneth N. | name-list-style = vanc | title = The First Structural Characterization of A Metal-Enterobactin Complex: [V(enterobactin)]2- | journal = Angewandte Chemie International Edition in English | volume = 31 | year = 1992 | pages = 466–468 | doi = 10.1002/anie.199204661 | issue = 4}}
{{cite journal |last1=Lee |first1=Chi Woo |last2=Ecker |first2=David J. |last3=Raymond |first3=Kenneth N. | name-list-style = vanc |year=1985 |title=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 |journal=J. Am. Chem. Soc. |volume=107 |issue=24 |pages=6920–6923 |doi=10.1021/ja00310a030 }}
}}
Category:Twelve-membered rings