A Siderophore (Greek for iron carrier) is an iron chelating compound secreted by microorganisms such as bacteria, fungi and grasses. . The bioavailability of iron Fe3+ ions is limited by the very low solubility of iron bearing mineral phases such as iron oxides at neutral pH and therefore cannot be utilized by organisms . Siderophores dissolve these mineral phases by formation of soluble Fe3+ complexes that can be taken up by active transport mechanisms. Many siderophores are nonribosomal peptides.

To put it another way: Under anoxic conditions, iron is generally in the +2 oxidation state (ferrous) and soluble. However, under oxic conditions, iron is generally in the +3 oxidation state (ferric) and forms various insoluble minerals. To obtain iron from such minerals, cells produce iron-binding siderophores that bind iron and transport it into the cell. One major group of siderophores consists of derivatives of hydroxamic acid, which chelate ferric iron very strongly.

Other strategies to enhance iron solubility and uptake are the acidification of the surrounding (e.g. used by plant roots) or the extracellular reduction of Fe3+ into the more soluble Fe2+ ions.

Examples of siderophores produced by various bacteria and fungi are ferrichrome (Ustilago sphaerogena), enterobactin (Escherichia coli), mycobactin (Mycobacterium), enterobactin and bacillibactin (Bacillus subtilis), ferrioxamine B (Streptomyces pilosus), fusarinine C (Fusarium roseum), yersiniabactin (Yersinia pestis), vibriobactin (Vibrio cholerae), azotobactin (Azotobacter vinelandii), pseudobactin (Pseudomonas B 10), erythrobactin (Saccharopolyspora erythraea) or ornibactin (Burkholderia cepacia). Some poaceae (grasses) including wheat and barley produce a class of sideorphores called phytosiderophores or mugineic acids.

Pseudomonas Siderophores Like all aerobic bacteria, pseudomonads need to take up iron via the secretion of siderophores which complex iron (III) with high affinity. Much progress has been made in the elucidation of siderophore-mediated high-affinity iron uptake by Pseudomonas, especially in the case of the opportunistic pathogen, P. aeruginosa. Fluorescent pseudomonads produce the high-affinity peptidic siderophore pyoverdine, but also, in many cases, a second siderophore of lesser affinity for iron. Some of the genes for the biosynthesis and uptake of these siderophores have been identified and the functions of the encoded proteins known. Iron uptake via siderophores is regulated at several levels, via the general iron-sensitive repressor Fur (Ferric Uptake Regulator), via extracytoplasmic sigma factors/anti-sigma factors or via other regulators. Since pseudomonads are ubiquitous microorganisms, it is not surprising to find in their genome a large number of genes encoding receptors for the uptake of heterologous ferrisiderophores or heme reflecting their great adaptability to diverse iron sources. Another exciting development is the recent evidence for a cross-talk between the iron regulon and other regulatory networks, including the diffusible signal molecule-mediated quorum sensing in P. aeruginosa.

Biological Function

In response to iron limitation in their environment, microbe siderophore production is derepressed. This is followed by excretion of the siderophore into the extracellular environment. Once outside the cell, the siderophore acts to sequester and solubilize the iron. Siderophores effectively bind with iron by forming an octahedral siderophore-iron complex. Siderophores are then recognized by cell specific receptors on the outer membrane of the cell. Following binding to these receptors they are transported across the cell membrane by a number of processes including but not limited to gating mechanisms and specific protein channels. The relatively weak complexation of Fe(II) affords an efficient pathway for iron release, via reduction of iron(III), inside the cell. Siderophore decomposition or other biological mechanisms can also release iron. The iron gained from siderophores is necessary for the proper function of the enzymes that facilitate electron transport, oxygen transport, and other life-sustaining processes. Bacteria and their host use structurally different siderophores in order to competitively bind iron and gain selective growth advantages over one another.

Structure and Identification

Hexadentate structures are the most common for siderophores. This is due to the requirement for three bidentate ligands which are often incorporated into the same molecule. The most effective siderophores contain multiple ligands. This allows for complete octahedral coordination of ferric ion, and the minimization of entropic effects caused by chelating a single ferric ion with separate ligands. Siderophores are almost specific for Fe(III) among the naturally occurring abundant metal ions. For a representative collection of siderophores see Studies and Syntheses of Siderophores, Microbial Iron Chelators, and Analogs as Potential Drug Delivery Agents by Marvin J. Miller.

Medical Applications

Siderophores have applications in medicine for iron and aluminum overload therapy and antibiotics for better targeting. Understanding the mechanistic pathways of siderophores has lead to opportunities for designing small-molecule inhibitors that block siderophore biosynthesis and therefore bacterial growth and virulence in iron-limiting environments.

Siderophores are useful as drugs in facilitating iron mobilization in humans, especially in the treatment of iron diseases, due to their high affinity for iron. One potentially powerful application is to use the iron transport abilities of siderophores to carry drugs into cells by preparation of conjugates between siderophores and antimicrobial agents. Because microbes recognize and utilize only certain siderophores, such conjugates are anticipated to have selective antimicrobial activity.

Microbial iron transport (siderophore)-mediated drug delivery makes use of the recognition of siderophores as iron delivery agents in order to have the microbe assimilate siderophore conjugates with attached drugs. These drugs are lethal to the microbe and cause the microbe to commit suicide when it assimilates the siderophore conjugate. Through the addition of the iron-binding functional groups of siderophores into antibiotics, their potency has been greatly increased. This is due to the siderophore-mediated iron uptake system of the bacteria.

Agricultural Applications

Poaceae (grasses) including agriculturally important species such as barley and wheat are able to efficiently sequester iron by releasing phytosiderophores via their root into the surrounding soil rhizosphere . Chemical compounds produced by microorganisms in the rhizosphere can also increase the availability and uptake of iron. Plants such as oats are able to assimilate iron via these microbial siderophores. It has been demonstrated that plants are able to use the hydroxamate-type siderophores ferrichrome, rodotorulic acid and ferrioxamine B; the catechol-type siderophores, agrobactin; and the mixed ligand catechol-hydroxamate-hydroxy acid siderophores biosynthesized by saprophytic root-colonizing bacteria. All of these compounds are produced by rhizospheric bacterial strains, which have simple nutritional requirements, and are found in nature in soils, foilage, fresh water, sediments, and seawater.

Fluorescent pseudomonads have been recongnized as biocontrol agents against certain soil-borne plant pathogens. They produce yellow-green pigments(pyoverdines) which fluoresce under UV light and function as siderophores. They deprive pathogens of the iron required for their growth and pathogenesis.

Other Metals Chelated by Siderophores

  • Aluminum
  • Gallium
  • Chromium
  • Copper
  • Zinc
  • Lead
  • Manganese
  • Cadmium
  • Vanadium
  • Indium
  • Plutonium
  • Uranium

Related Processes

Alternative means of assimilating iron are surface reduction, lowering of pH, utilization of heme, or extraction of protein-complexed metal.


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