Enterobactin

Last updated
Enterobactin
Enterobactin.svg
Names
Preferred IUPAC name
N,N′,N′′-[(3S,7S,11S)-2,6,10-Trioxo-1,5,9-trioxacyclododecane-3,7,11-triyl]tris(2,3-dihydroxybenzamide)
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
PubChem CID
UNII
  • InChI=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 Yes check.svgY
    Key: SERBHKJMVBATSJ-BZSNNMDCSA-N Yes check.svgY
  • 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
    Key: SERBHKJMVBATSJ-BZSNNMDCBT
  • 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
  • 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
Properties
C30H27N3O15
Molar mass 669.55 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

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]

Contents

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. [The synthesis image structure in middle should be DihydroxyBenzoicAcid, incorrectly chorismic acid is shown]. 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]

Enterobactin synthesis.png

Mechanism

Iron deficiency in bacterial cells triggers secretion of enterobactin into the extracellular environment, causing formation of a coordination complex "FeEnt" wherein ferric ion 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. [7] 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. [8]

History

Enterobactin was discovered by Gibson and Neilands groups in 1970. [9] [10] These initial studies established the structure and its relationship to 2,3-dihydroxybenzoic acid.

Related Research Articles

<span class="mw-page-title-main">Siderophore</span> Iron compounds secreted by microorganisms

Siderophores (Greek: "iron carrier") are small, high-affinity iron-chelating compounds that are secreted by microorganisms such as bacteria and fungi. They help the organism accumulate iron. Although a widening range of siderophore functions is now being appreciated, siderophores are among the strongest (highest affinity) Fe3+ binding agents known. Phytosiderophores are siderophores produced by plants.

<span class="mw-page-title-main">Chorismic acid</span> Chemical compound

Chorismic acid, more commonly known as its anionic form chorismate, is an important biochemical intermediate in plants and microorganisms. It is a precursor for:

<span class="mw-page-title-main">Acetolactate synthase</span> Class of enzymes

The acetolactate synthase (ALS) enzyme is a protein found in plants and micro-organisms. ALS catalyzes the first step in the synthesis of the branched-chain amino acids.

<span class="mw-page-title-main">Maltose-binding protein</span>

Maltose-binding protein (MBP) is a part of the maltose/maltodextrin system of Escherichia coli, which is responsible for the uptake and efficient catabolism of maltodextrins. It is a complex regulatory and transport system involving many proteins and protein complexes. MBP has an approximate molecular mass of 42.5 kilodaltons.

In enzymology, a 2,3-dihydro-2,3-dihydroxybenzoate dehydrogenase (EC 1.3.1.28) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Outer membrane receptor</span>

Outer membrane receptors, also known as TonB-dependent receptors, are a family of beta barrel proteins named for their localization in the outer membrane of gram-negative bacteria. TonB complexes sense signals from the outside of bacterial cells and transmit them into the cytoplasm, leading to transcriptional activation of target genes. TonB-dependent receptors in gram-negative bacteria are associated with the uptake and transport of large substrates such as iron siderophore complexes and vitamin B12.

<span class="mw-page-title-main">Aerobactin</span> Chemical compound

Aerobactin is a bacterial iron chelating agent (siderophore) found in E. coli. It is a virulence factor enabling E. coli to sequester iron in iron-poor environments such as the urinary tract.

2,3-Dihydroxybenzoic acid is a natural phenol found in Phyllanthus acidus and in the aquatic fern Salvinia molesta. It is also abundant in the fruits of Flacourtia inermis. It is a dihydroxybenzoic acid, a type of organic compound. The colorless solid occurs naturally, being formed via the shikimate pathway. It is incorporated into various siderophores, which are molecules that strongly complex iron ions for absorption into bacteria. 2,3-DHB consists of a catechol group, which upon deprotonation binds iron centers very strongly, and the carboxylic acid group by which the ring attaches to various scaffolds through amide bonds. A famous high affinity siderophore is enterochelin, which contains three dihydroxybenzoyl substituents linked to the depsipeptide of serine.

<span class="mw-page-title-main">Ferrichrome</span> Chemical compound

Ferrichrome is a cyclic hexa-peptide that forms a complex with iron atoms. It is a siderophore composed of three glycine and three modified ornithine residues with hydroxamate groups [-N(OH)C(=O)C-]. The 6 oxygen atoms from the three hydroxamate groups bind Fe(III) in near perfect octahedral coordination.

<span class="mw-page-title-main">Rhodotorulic acid</span> Chemical compound

Rhodotorulic acid is the smallest of the 2,5-diketopiperazine family of hydroxamate siderophores which are high-affinity chelating agents for ferric iron, produced by bacterial and fungal phytopathogens for scavenging iron from the environment. It is a tetradentate ligand, meaning it binds one iron atom in four locations (two hydroxamate and two lactam moieties), and forms Fe2(siderophore)3 complexes to fulfill an octahedral coordination for iron.

<span class="mw-page-title-main">Yersiniabactin</span> Chemical compound

Yersiniabactin (Ybt) is a siderophore found in the pathogenic bacteria Yersinia pestis, Yersinia pseudotuberculosis, and Yersinia enterocolitica, as well as several strains of enterobacteria including enteropathogenic Escherichia coli and Salmonella enterica. Siderophores, compounds of low molecular mass with high affinities for ferric iron, are important virulence factors in pathogenic bacteria. Iron—an essential element for life used for such cellular processes as respiration and DNA replication—is extensively chelated by host proteins like lactoferrin and ferritin; thus, the pathogen produces molecules with an even higher affinity for Fe3+ than these proteins in order to acquire sufficient iron for growth. As a part of such an iron-uptake system, yersiniabactin plays an important role in pathogenicity of Y. pestis, Y. pseudotuberculosis, and Y. entercolitica.

<span class="mw-page-title-main">2,6-Pyridinedicarbothioic acid</span> Chemical compound

2,6-Pyridinedicarbothioic acid (PDTC) is an organosulfur compound that is produced by some bacteria. It functions as a siderophore, a small chelating agent with a high affinity for iron. Siderophores are deployed as ion scavengers for microbes. Siderophores solubilize compounds by forming strong complexes. PDTC is secreted by the soil bacteria Pseudomonas stutzeri and Pseudomonas putida.

Many bacteria secrete small iron-binding molecules called siderophores, which bind strongly to ferric ions. FepA is an integral bacterial outer membrane porin protein that belongs to outer membrane receptor family and provides the active transport of iron bound by the siderophore enterobactin from the extracellular space, into the periplasm of Gram-negative bacteria. FepA has also been shown to transport vitamin B12, and colicins B and D as well. This protein belongs to family of ligand-gated protein channels.

<span class="mw-page-title-main">Ascorbate ferrireductase (transmembrane)</span> Class of enzymes

Ascorbate ferrireductase (transmembrane) (EC 1.16.5.1, cytochrome b561) is an enzyme with systematic name Fe(III):ascorbate oxidorectuctase (electron-translocating). This enzyme catalyses the following chemical reaction

N2-citryl-N6-acetyl-N6-hydroxylysine synthase (EC 6.3.2.38, N(alpha)-citryl-N(epsilon)-acetyl-N(epsilon)-hydroxylysine synthase, iucA (gene)) is an enzyme with systematic name citrate:N6-acetyl-N6-hydroxy-L-lysine ligase (ADP-forming). This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Bacillibactin</span> Chemical compound

Bacillibactin is a catechol-based siderophore secreted by members of the genus Bacillus, including Bacillus anthracis and Bacillus subtilis. It is involved in the chelation of ferric iron (Fe3+) from the surrounding environment and is subsequently transferred into the bacterial cytoplasm via the use of ABC transporters.

Siderocalin(Scn), lipocalin-2, NGAL, 24p3 is a mammalian lipocalin-type protein that can prevent iron acquisition by pathogenic bacteria by binding siderophores, which are iron-binding chelators made by microorganisms. Iron serves as a key nutrient in host-pathogen interactions, and pathogens can acquire iron from the host organism via synthesis and release siderophores such as enterobactin. Siderocalin is a part of the mammalian defence mechanism and acts as an antibacterial agent. Crystallographic studies of Scn demonstrated that it includes a calyx, a ligand-binding domain that is lined with polar cationic groups. Central to the siderophore/siderocalin recognition mechanism are hybrid electrostatic/cation-pi interactions. To evade the host defences, pathogens evolved to produce structurally varied siderophores that would not be recognized by siderocalin, allowing the bacteria to acquire iron.

The iron/lead transporter (ILT) family is a family of transmembrane proteins within the lysine exporter (LysE) superfamily. The ILT family includes two subfamilies, the iron-transporting (OFeT) family and the lead-transporting (PbrT) family. A representative list of the proteins belonging to these subfamilies of the ILT family can be found in the Transporter Classification Database.

<span class="mw-page-title-main">Rebecca Abergel</span> French inorganic chemist

Rebecca Abergel is a French inorganic chemist who specializes in the coordination chemistry between lanthanide and actinide complexes. Alongside the effects of heavy element exposure and contamination on different biological systems. Abergel is currently a Faculty Scientist and Heavy Element Chemistry Group Leader at the Chemical Sciences Division of Lawrence Berkeley National Laboratory in Berkeley, California. She is also Assistant Professor of Nuclear Engineering at University of California, Berkeley.

<span class="mw-page-title-main">Vibriobactin</span> Chemical compound

Vibriobactin is a catechol siderophore that helps the microbial system to acquire iron. It was first isolated from Vibrio cholerae.

References

  1. Dertz EA, Xu J, Stintzi A, Raymond KN (January 2006). "Bacillibactin-mediated iron transport in Bacillus subtilis". Journal of the American Chemical Society. 128 (1): 22–3. doi:10.1021/ja055898c. PMID   16390102.
  2. Carrano CJ, Raymond KN (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.
  3. 1 2 Walsh CT, Liu J, Rusnak F, Sakaitani M (1990). "Molecular Studies on Enzymes in Chorismate Metabolism and the Enterobactin Biosynthetic Pathway". Chemical Reviews . 90 (7): 1105–1129. doi:10.1021/cr00105a003.
  4. 1 2 Raymond KN, Dertz EA, Kim SS (April 2003). "Enterobactin: an archetype for microbial iron transport". Proceedings of the National Academy of Sciences of the United States of America. 100 (7): 3584–8. doi: 10.1073/pnas.0630018100 . PMC   152965 . PMID   12655062.
  5. Karpishin TB, Raymond KN (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. Johnstone TC, Nolan EM (October 2017). "Determination of the Molecular Structures of Ferric Enterobactin and Ferric Enantioenterobactin Using Racemic Crystallography". Journal of the American Chemical Society. 139 (42): 15245–15250. doi:10.1021/jacs.7b09375. PMC   5748154 . PMID   28956921.
  7. Ward TR, Lutz A, Parel SP, Ensling J, Gütlich P, Buglyó P, Orvig C (November 1999). "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. doi:10.1021/ic990225e. PMID   11671244.
  8. Lee CW, Ecker DJ, Raymond KN (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.
  9. Pollack JR, Neilands JB (March 1970). "Enterobactin, an iron transport compound from Salmonella typhimurium". Biochemical and Biophysical Research Communications. 38 (5): 989–92. doi:10.1016/0006-291X(70)90819-3. PMID   4908541.
  10. O'Brien IG, Cox GB, Gibson F (March 1970). "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. doi:10.1016/0304-4165(70)90165-0. PMID   4908639.