Siderophores (
Greek: "iron carrier") are small, high-affinity
ironIron is a metallic chemical element with the symbol Fe and atomic number 26. Iron is a group 8 and period 4 element and is therefore classified as a transition metal. Iron and iron alloys are by far the most common metals and the most common ferromagnetic materials in everyday use...
chelatingChelation is the formation or presence of two or more separate bindings between apolydentate ligand and a single central atom.Usually these ligands are organic compounds, and are called chelants, chelators, chelating agents, or sequestering agents....
compounds secreted by
microorganismA microorganism or microbe is an organism that is microscopic...
s such as bacteria, fungi and grasses. . Siderophores are amongst the strongest soluble Fe
3+ binding agents known.
The scarcity of soluble iron
Iron is essential for almost all life, essential for processes such as respiration and DNA synthesis. Despite being one of the most abundant elements in the Earth’s crust, the bioavailability of iron in many environments such as the soil or sea is limited by the very low
solubilitySolubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a liquid solvent to form a homogeneous solution. The solubility of a substance strongly depends on the used solvent as well as on temperature and pressure...
of the Fe
3+ ion. This is the predominant state of iron in aqueous, non-acidic, oxygenated environments. It accumulates in common mineral phases such as iron oxides and hydroxides (the minerals that are responsible for red and yellow soil colours) hence cannot be readily utilized by organisms. Microbes release siderophores to scavenge iron from these mineral phases by formation of soluble
Fe3+Iron is a metallic chemical element with the symbol Fe and atomic number 26. Iron is a group 8 and period 4 element and is therefore classified as a transition metal. Iron and iron alloys are by far the most common metals and the most common ferromagnetic materials in everyday use...
complexIn chemistry, a coordination complex or metal complex, is a structure consisting of a central atom or ion , bonded to a surrounding array of molecules or anions ....
es that can be taken up by
active transportActive transport is the mediated process of moving particles across a biological membrane against a concentration gradient. If the process uses chemical energy, such as from adenosine triphosphate , it is termed primary active transport. Secondary active transport involves the use of an...
mechanisms. Many siderophores are
nonribosomal peptideNonribosomal peptides are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacteria inside these organisms...
s, although several are biosynthesised independently.
Siderophores are also important for some pathogenic bacteria for their acquisition of iron. In mammalian hosts, iron is tightly bound to proteins such as
hemoglobinHemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of vertebrates, and the tissues of some invertebrates....
,
transferrinTransferrin is a blood plasma protein for iron ion delivery that, in humans, is encoded by the TF gene. Transferrin is a glycoprotein that binds iron very tightly but reversibly. Although iron bound to transferrin is less than 0.1% of the total body iron, it is the most important iron pool, with...
,
lactoferrinLactoferrin , also known as lactotransferrin , is a globular multifunctional protein with antimicrobial activity and is part of the innate defense, mainly at mucoses. Lactoferrin is found in milk and many mucosal secretions such as tears and saliva. Lactoferrin is also present in secondary...
and
ferritinFerritin is a globular protein complex consisting of 24 protein subunits and is the primary intracellular iron-storage protein in both prokaryotes and eukaryotes, keeping iron in a soluble and non-toxic form...
. The strict homeostasis of iron leads to a free concentration of about 10
-24 mol L
-1, hence there are great evolutionary pressures put on pathogenic bacteria to obtain this metal. For example, the
anthraxAnthrax is an acute disease caused by Bacillus anthracis. It affects both humans and animals. Most forms of the disease are highly lethal...
pathogen
Bacillus anthracis releases two siderophores, bacillibactin and petrobactin, to scavenge ferric iron from iron proteins. Whilst bacillibactin has been shown to bind to the immune system protein
siderocalinSiderocalin is a protein that is produced by the body in response to bacterial infection. During an infection, bacteria produce iron-chelators called siderophores, which are used for 'stealing' iron from the host...
, petrobactin is assumed to evade the immune system and has been shown to be important for virulence in mice.
Siderophores are amongst the strongest binders to Fe
3+ known, with
enterobactinEnterobactin 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....
being one of the strongest of these. Because of this property, they have attracted interest from medical science in metal
chelation therapyChelation therapy is the administration of chelating agents to remove heavy metals from the body. For the most common forms of heavy metal intoxication—those involving lead, arsenic or mercury—the standard of care in the USA dictates the use of dimercaptosuccinic acid...
, with the siderophore
desferrioxamine BDeferoxamine is a bacterial siderophore produced by the actinobacter Streptomyces pilosus. It has medical applications as a chelating agent used to remove excess iron from the body...
gaining widespread use in treatments for
iron poisoningIron poisoning is caused by a large excess of iron intake. It has been primarily been associated with young children who consumed large quantities of iron supplement pills, which resemble sweets and are widely used, including by pregnant women. Iron poisoning is caused by a large excess of iron...
and
thalassemiaThalassemia is an inherited autosomal co-dominant blood disease. In thalassemia, the genetic defect results in reduced rate of synthesis of one of the globin chains that make up hemoglobin...
.
Besides siderophores, some pathogenic bacteria produce
hemophores (
hemeA heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin...
binding scavenging proteins) or have receptors that bind directly to iron/heme proteins. In eukaryotes, other strategies to enhance iron solubility and uptake are the
acidAn acid is traditionally considered any chemical compound that, when dissolved in water, gives a solution with a hydrogen ion activity greater than in pure water, i.e. a pH less than 7.0...
ification of the surrounding (e.g. used by plant roots) or the
extracellularIn cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
reduction of
Fe3+Iron is a metallic chemical element with the symbol Fe and atomic number 26. Iron is a group 8 and period 4 element and is therefore classified as a transition metal. Iron and iron alloys are by far the most common metals and the most common ferromagnetic materials in everyday use...
into the more soluble
Fe2+Iron is a metallic chemical element with the symbol Fe and atomic number 26. Iron is a group 8 and period 4 element and is therefore classified as a transition metal. Iron and iron alloys are by far the most common metals and the most common ferromagnetic materials in everyday use...
ions.
Structure and Identification
Siderophores usually form a stable, hexadentate, octahedral complex with Fe
3+ preferentially compared to other naturally occurring abundant metal ions, although if there are less than six donor atoms water can also coordinate. The most effective siderophores are those that have three bidentate
ligandIn chemistry, a ligand is either an atom, ion, or molecule that binds to a central metal-atom to produce a coordination complex. The bonding between the metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The metal-ligand bonding ranges from covalent...
s per molecule, forming a hexadentate complex and causing a smaller entropic change than that caused by chelating a single ferric ion with separate ligands. 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.
Fe
3+ is a hard
Lewis acidA Lewis acid, A, is a chemical compound that can accept a pair of electrons from a Lewis base, B, that acts as an electron-pair donor, forming an adduct, AB:
A + :B → A—B...
, preferring hard Lewis bases such as anionic or neutral oxygen to coordinate with. Microbes usually release the iron from the siderophore by reduction to Fe
2+ which has little affinity to these ligands.
Siderophores are usually classified by the ligands used to chelate the ferric iron. The major groups of siderophores include the catecholates (phenolates),
hydroxamateA hydroxamic acid is a class of chemical compounds sharing the same functional group in which an hydroxylamine is inserted into a carboxylic acid. Its general structure is R-CO-NH-OH, with an R as an organic residue, a CO as a carbonyl group, and a hydroxylamine as NH2-OH...
s and carboxylates (e.g. derivatives of
citric acidCitric acid is a weak organic acid, and it is a natural preservative and is also used to add an acidic, or sour, taste to foods and soft drinks. In biochemistry, it is important as an intermediate in the citric acid cycle and therefore occurs in the metabolism of virtually all living things...
). Citric acid can also act as a siderophore. The wide variety of siderophores may be due to evolutionary pressures placed on microbes to produce structurally different siderophores which cannot be transported by other microbes' specific active transport systems, or in the case of pathogens deactivated by the host organism.
Diversity
Examples of siderophores produced by various bacteria and fungi:
Hydroxamate siderophores
| Siderophore |
Organism |
| ferrichrome Ferrichrome is a cyclic hexa-peptide that forms a complex with iron atoms.Ferrichrome was first isolated in 1952, has been found to be produced by fungi of the genera Aspergillus, Ustilago, and Penicillium....
|
UstilagoUstilago is a genus of smut fungi parasitic on grasses.There is a large research community that works on Ustilago maydis including researchers at the University of Georgia,Philipps-Universität Marburg, University of British Columbia and others....
sphaerogena |
Desferrioxamine B
(DeferoxamineDeferoxamine is a bacterial siderophore produced by the actinobacter Streptomyces pilosus. It has medical applications as a chelating agent used to remove excess iron from the body...
) |
StreptomycesStreptomyces is the largest genus of Actinobacteria and the type genus of the family Streptomycetaceae. Over 500 species of Streptomyces bacteria have been described. As with the other Actinobacteria, streptomycetes are gram-positive, and have genomes with high GC-content...
pilosus
StreptomycesStreptomyces is the largest genus of Actinobacteria and the type genus of the family Streptomycetaceae. Over 500 species of Streptomyces bacteria have been described. As with the other Actinobacteria, streptomycetes are gram-positive, and have genomes with high GC-content...
coelicolor |
| Desferrioxamine E |
StreptomycesStreptomyces is the largest genus of Actinobacteria and the type genus of the family Streptomycetaceae. Over 500 species of Streptomyces bacteria have been described. As with the other Actinobacteria, streptomycetes are gram-positive, and have genomes with high GC-content...
coelicolor |
| fusarinine C |
FusariumFusarium is a large genus of filamentous fungi widely distributed in soil and in association with plants. Most species are harmless saprobes and are relatively abundant members of the soil microbial community. Some species produce mycotoxins in cereal crops that can affect human and animal health...
roseum |
| ornibactin |
Burkholderia cepacia |
Catecholate siderophores
| Siderophore |
Organism |
enterobactinEnterobactin 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....
|
Escherichia coliEscherichia coli , is a Gram negative bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E...
enteric bacteria |
| bacillibactin |
Bacillus subtilisBacillus subtilis, known as the hay bacillus or grass bacillus, is a Gram-positive, catalase-positive bacterium commonly found in soil. A member of the genus Bacillus, B. subtilis is rod-shaped, and has the ability to form a tough, protective endospore, allowing the organism to tolerate extreme...
Bacillus anthracisBacillus anthracis is a Gram-positive spore-forming, rod-shaped bacterium, with a width of 1-1.2µm and a length of 3-5µm. It can be grown in an ordinary nutrient medium under aerobic or anaerobic conditions. It is the only bacterium with a protein capsule , and the only pathogenic bacteria to...
|
| vibriobactin |
Vibrio choleraeVibrio cholerae is a motile gram negative curved-rod shaped bacterium with a polar flagellum that causes cholera in humans. V. cholerae and other species of the genus Vibrio belong to the gamma subdivision of the Proteobacteria. There are two major strains of V. cholerae, classic and El Tor,...
|
Mixed ligands
| Siderophore |
Organism |
| azotobactin |
Azotobacter vinelandii Azotobacter vinelandii is a diazotroph that can fix nitrogen while grown aerobically. It is a genetically tractable system that is used to study nitrogen fixation...
|
| pyoverdine |
Pseudomonas aeruginosaPseudomonas aeruginosa is a common bacterium which can cause disease in animals and humans. It is found in soil, water, skin flora and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also with little oxygen, and has thus colonised many natural and...
|
| yersiniabactin |
Yersinia pestisYersinia pestis is a Gram-negative rod-shaped bacterium belonging to the family Enterobacteriaceae. It is a facultative anaerobe that can infect humans and other animals....
|
Some
poaceaePoaceae or Gramineae is a family in the Class Liliopsida of the flowering plants. Plants of this family are usually called grasses, or, to distinguish them from other graminoids, true grasses; the shrub- or tree-like plants in this family are called bamboo...
(grasses) including
wheatWheat is a worldwide cultivated grass from the Fertile Crescent region of the Near East. In 2007 world production of wheat was 607 million tons, making it the third most-produced cereal after maize and rice...
and
barleyBarley is a cereal grain derived from the annual grass Hordeum vulgare. It serves as a major animal feed crop, with smaller amounts used for malting and in health food. It is used in soups, stews and barley bread in various countries, such as Scotland and in Africa...
produce a class of sideorphores called phytosiderophores or mugineic acids.
Biological Function
In response to iron limitation in their environment, genes involved in microbe siderophore production and uptake are derepressed, leading to manufacture of siderophores and the appropriate uptake proteins. In bacteria, Fe
2+-dependent repressors bind to DNA upstream to genes involved in siderophore in high intracellular iron concentrations. At low concentrations, Fe
2+ dissociates from the repressor, which in turn dissociates from the DNA, leading to transcription of the genes. In gram-negative and AT-rich gram-positive bacteria, this is usually regulated by the
Fur (ferric uptake regulator) repressor, whilst in GC-rich gram-positive bacteria (e.g
ActinobacteriaActinobacteria are a group of Gram-positive bacteria with high G+C ratio. They can be terrestrial or aquatic.Use of the ferric uptake regulator has been suggested for classification...
) it is
DtxR (diphtheria toxin repressor), so-called as the production of the dangerous
diphtheria toxinDiphtheria toxin is an exotoxin secreted by Corynebacterium diphtheriae, the pathogen bacterium that causes diphtheria.-Structure:Diphtheria toxin is a single polypeptide chain of 535 amino acids consisting of two subunits linked by disulfide bridges...
by
Corynebacterium diphtheriaeCorynebacterium diphtheriae is a pathogenic bacterium that causes diphtheria. It is also known as the Klebs-Löffler bacillus, because it was discovered in 1884 by German bacteriologists Edwin Klebs and Friedrich Löffler .-Classification:Four subspecies are recognized: C. diphtheriae mitischodis,...
is also regulated by this system.
This is followed by excretion of the siderophore into the extracellular environment, where the siderophore acts to sequester and solubilize the iron. Siderophores are then recognized by cell specific receptors on the outer membrane of the cell. In fungi and other eukaryotes, the Fe-siderophore complex may be extracellularly reduced to Fe
2+, whilst in many cases the whole Fe-siderophore complex is actively transported across the cell membrane. In gram-negative bacteria, these are transported into the cell via
TonB-dependent receptorsTonB-dependent receptors is a family of beta-barrel proteins from the outer membrane of Gram-negative bacteria. The TonB complex senses signals from outside the bacterial cell and transmits them via two membranes into the cytoplasm, leading to transcriptional activation of target genes.In...
, whilst in gram-positive bacteria this role is fulfilled by ABC transporters.
Once in the cytoplasm of the cell, the Fe
3+-siderophore complex is usually reduced to Fe
2+ to release the iron, especially in the case of "weaker" siderophore ligands such as hydroxamates and carboxylates. Siderophore decomposition or other biological mechanisms can also release iron. , especially in the case of catecholates such as ferric-enterobactin, whose reduction potential is too low for reducing agents such as flavin adenine dinucleotide, hence enzymatic degradation is needed to release the iron.
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 led 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
PoaceaePoaceae or Gramineae is a family in the Class Liliopsida of the flowering plants. Plants of this family are usually called grasses, or, to distinguish them from other graminoids, true grasses; the shrub- or tree-like plants in this family are called bamboo...
(grasses) including agriculturally important species such as
barleyBarley is a cereal grain derived from the annual grass Hordeum vulgare. It serves as a major animal feed crop, with smaller amounts used for malting and in health food. It is used in soups, stews and barley bread in various countries, such as Scotland and in Africa...
and
wheatWheat is a worldwide cultivated grass from the Fertile Crescent region of the Near East. In 2007 world production of wheat was 607 million tons, making it the third most-produced cereal after maize and rice...
are able to efficiently sequester iron by releasing phytosiderophores via their
rootIn vascular plants, the root is the organ of a plant that typically lies below the surface of the soil. This is not always the case, however, since a root can also be aerial or aerating . Furthermore, a stem normally occurring below ground is not exceptional either...
into the surrounding
soilSoil is a natural body consisting of layers of mineral constituents of variable thicknesses, which differ from the parent materials in their morphological, physical, chemical, and mineralogical characteristics. It is composed of particles of broken rock that have been altered by chemical and...
rhizosphereThe rhizosphere is the narrow region of soil that is directly influenced by root secretions and associated soil microorganisms. Soil which is not part of the rhizosphere is known as bulk soil. The rhizosphere contains many bacteria that feed on sloughed-off plant cells, termed rhizodeposition, and...
. 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, foliage, 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
Related Processes
Alternative means of assimilating iron are surface reduction, lowering of pH, utilization of heme, or extraction of protein-complexed metal.