Enterobactin (also known as enterochelin) is a high affinity

siderophore 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 no ...

that acquires

iron Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in f ...

for microbial systems. It is primarily found in

Gram-negative Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...

bacteria, such as ''

Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...

'' and ''

Salmonella typhimurium ''Salmonella enterica'' subsp. ''enterica'' is a subspecies of ''Salmonella enterica'', the rod-shaped, flagellated, aerobic, Gram-negative bacterium. Many of the pathogenic serovars of the ''S. enterica'' species are in this subspecies, includi ...

''. Enterobactin is the strongest siderophore known, binding to the ferric ion (Fe³⁺) with

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Par ...

K = 10⁵² M⁻¹. This value is substantially larger than even some synthetic metal

chelator Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These ligands are ...

s, such as

EDTA Ethylenediaminetetraacetic acid (EDTA) is an aminopolycarboxylic acid with the formula H2N(CH2CO2H)2sub>2. This white, water-soluble solid is widely used to bind to iron (Fe2+/Fe3+) and calcium ions (Ca2+), forming water-soluble complexes eve ...

(K_f,Fe3+ ~ 10²⁵ M⁻¹). Due to its high affinity, enterobactin is capable of

chelating Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a Denticity, polydentate (multiple bonded) ligand and a single central metal atom. These l ...

even in environments where the concentration of ferric ion is held very low, such as within living organisms. Enterobactin can extract iron even from the

air The atmosphere of Earth is the layer of gases, known collectively as air, retained by Earth's gravity that surrounds the planet and forms its planetary atmosphere. The atmosphere of Earth protects life on Earth by creating pressure allowing f ...

Pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...

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 Chorismic acid, more commonly known as its anionic form chorismate, is an important biochemical intermediate in plants and microorganisms. It is a precursor for: * The aromatic amino acids phenylalanine, tryptophan, and tyrosine * Indole, indole d ...

, an aromatic

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

precursor Precursor or Precursors may refer to: *Precursor (religion), a forerunner, predecessor ** The Precursor, John the Baptist Science and technology * Precursor (bird), a hypothesized genus of fossil birds that was composed of fossilized parts of unr ...

, is converted to 2,3-dihydroxybenzoic acid (DHB) by a series of

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

s, EntA, EntB and EntC. An

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...

linkage of DHB to

L-serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form ...

is then catalyzed by EntD, EntE, EntF and EntB. Three molecules of the DHB-Ser formed undergo

intermolecular cyclization An intermolecular force (IMF) (or secondary force) is the force that mediates interaction between molecules, including the electromagnetic forces of attraction or repulsion which act between atoms and other types of neighbouring particles, e.g. a ...

, yielding enterobactin. Although a number of

stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...

s are possible due to the

chirality Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from ...

of the serine residues, only the Δ-cis

isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. Iso ...

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.

Mechanism

Iron deficiency Iron deficiency, or sideropenia, is the state in which a body lacks enough iron to supply its needs. Iron is present in all cells in the human body and has several vital functions, such as carrying oxygen to the tissues from the lungs as a key ...

in bacterial cells triggers secretion of enterobactin into the extracellular environment, causing formation of a

coordination complex A coordination complex consists of a central atom or ion, which is usually metallic and is called the ''coordination centre'', and a surrounding array of bound molecules or ions, that are in turn known as ''ligands'' or complexing agents. Many ...

" FeEnt" wherein ferric ion is chelated to the conjugate base of enterobactin. In ''

'', FepA in the bacterial outer membrane then allows entrance of FeEnt to the bacterial

periplasm The periplasm is a concentrated gel-like matrix in the space between the inner cytoplasmic membrane and the bacterial outer membrane called the ''periplasmic space'' in gram-negative bacteria. Using cryo-electron microscopy it has been found that ...

. FepB,C,D and G all participate in transport of the FeEnt through the inner membrane by means of an

ATP-binding cassette transporter The ATP-binding cassette transporters (ABC transporters) are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC transp ...

. 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 The standard hydrogen electrode (abbreviated SHE), is a redox electrode which forms the basis of the thermodynamic scale of oxidation-reduction potentials. Its absolute electrode potential is estimated to be at 25 °C, but to form a basis ...

) at pH 6 to −0.79 V at pH 7.4 to −0.99 at pH values higher than 10.4.

History

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

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. The ''Journal of the American Chemical Society'' is a weekly peer-reviewed scientific journal that was established in 1879 by the American Chemical Society. The journal has absorbed two other publications in its history, the ''Journal of Analytic ...

, 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 ''Chemical Reviews'' is peer-reviewed scientific journal published twice per month by the American Chemical Society. It publishes review articles on all aspects of chemistry. It was established in 1924 by William Albert Noyes (University of Illinoi ...

, 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: (enterobactin)- , journal =

Angewandte Chemie International Edition in English ''Angewandte Chemie'' (, meaning "Applied Chemistry") is a weekly peer-reviewed scientific journal that is published by Wiley-VCH on behalf of the German Chemical Society (Gesellschaft Deutscher Chemiker). Publishing formats include feature-length ...

, volume = 31 , year = 1992 , pages = 466–468 , doi = 10.1002/anie.199204661 , issue = 4 {{cite journal , vauthors = Raymond KN, Dertz EA, Kim SS , title = Enterobactin: an archetype for microbial iron transport , journal = Proceedings of the National Academy of Sciences of the United States of America , volume = 100 , issue = 7 , pages = 3584–8 , date = April 2003 , pmid = 12655062 , pmc = 152965 , doi = 10.1073/pnas.0630018100 , doi-access = free {{cite journal , vauthors = Ward TR, Lutz A, Parel SP, Ensling J, Gütlich P, Buglyó P, Orvig C , title = An Iron-Based Molecular Redox Switch as a Model for Iron Release from Enterobactin via the Salicylate Binding Mode , journal = Inorganic Chemistry , volume = 38 , issue = 22 , pages = 5007–5017 , date = November 1999 , pmid = 11671244 , doi = 10.1021/ic990225e {{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=

, volume=107 , issue=24 , pages=6920–6923 , doi=10.1021/ja00310a030 {{cite journal , vauthors = O'Brien IG, Cox GB, Gibson F , title = Biologically active compounds containing 2,3-dihydroxybenzoic acid and serine formed by Escherichia coli , journal = Biochimica et Biophysica Acta (BBA) - General Subjects , volume = 201 , issue = 3 , pages = 453–60 , date = March 1970 , pmid = 4908639 , doi = 10.1016/0304-4165(70)90165-0 {{cite journal , vauthors = Pollack JR, Neilands JB , title = Enterobactin, an iron transport compound from Salmonella typhimurium , journal = Biochemical and Biophysical Research Communications , volume = 38 , issue = 5 , pages = 989–92 , date = March 1970 , pmid = 4908541 , doi = 10.1016/0006-291X(70)90819-3 Macrocycles Siderophores Salicylamides Lactones