Siderophores are compounds produced by bacteria, fungi and graminaceous plants for scavenging iron from the environment. They are low-molecular-weight compounds (500-1500 daltons) possessing a high affinity for iron(III) (Kf > 1030), the biosynthesis of which is regulated by iron levels and the function of which is to supply iron to the cell. This article briefly describes the classification and chemical properties of siderophores, before outlining research on siderophore biosynthesis and transport. Clinically important siderophores and the therapeutic potential of siderophore design are described. Appendix 1 provides a comprehensive list of siderophore structures.

Pseudomonas aeruginosa produces 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS), a quorum-sensing (QS) signal that regulates numerous virulence genes including those involved in iron scavenging. Biophysical analysis revealed that 2-alkyl-3-hydroxy-4-quinolones form complexes with iron(III) at physiological pH. The overall stability constant of 2-methyl-3-hydroxy-4-quinolone iron(III) complex was log beta(3) = 36.2 with a pFe(3+) value of 16.6 at pH 7.4. PQS was found to operate via at least three distinct signaling pathways, and its precursor, 2-heptyl-4-quinolone (HHQ), which does not form an iron complex, was discovered to function as an autoinducer molecule per se. When PQS was supplied to a P. aeruginosa mutant unable to make pyoverdine or pyochelin, PQS associated with the cell envelope and inhibited bacterial growth, a finding that reveals a secondary function for PQS in iron entrapment to facilitate siderophore-mediated iron delivery.

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Citrate is an iron chelator and it has been shown to be the major iron ligand in the xylem sap of plants. Furthermore, citrate has been demonstrated to be an important ligand for the non-transferrin bound iron (NTBI) pool occurring in the plasma of individuals suffering from iron-overload. However, ferric citrate chemistry is complicated and a definitive description of its aqueous speciation at neutral pH remains elusive. X-Ray crystallography data indicates that the alcohol function of citrate (Cit4-) is involved in Fe(III) coordination and that deprotonation of this functional group occurs upon complex formation. The inability to include this deprotonation in the affinity constant calculations has been a major source of divergence between various reports of iron(III)-citrate affinity constants. However the recent determination of the alcoholic pKa of citric acid (H4Cit) renders the reassessment of the ferric citrate system possible. The aqueous speciation of ferric citrate has been investigated by mass spectrometry and EPR spectroscopy. It was observed that the most relevant species are a monoiron dicitrate species and dinuclear and trinuclear oligomeric complexes, the relative concentration of which depends on the solution pH value and the iron : citric acid molar ratio. Spectrophotometric titration was utilized for affinity constant determination and the formation constant for the biologically relevant [Fe(Cit)2]5- is reported for the first time.

The cytoplasmic labile iron pool supplies iron to the mitochondrion for heme and iron sulfur cluster synthesis and to many cytoplasmic enzymes, thereby controlling numerous metabolic reactions. Surprisingly the chemical nature of this pool has never been convincingly characterised. Here we provide evidence for iron(II)glutathione being the dominant component of this pool. We report for the first time the affinity constant for the glutathione-iron(II) interaction and use this value to study the cytoplasmic speciation of iron(II). The formation of this complex is a major determinant of the electrode potential of the cytoplasmic ferrous iron pool, a means of selecting between iron(II) and manganese(II) and it provides a substrate for glutaredoxin/iron clusters at the dimer interface of glutaredoxins involved in the synthesis of Fe-S cluster proteins.

A range of iron binding dendrimers terminated with hexadentate ligands formed from hydroxypyridinone, hydroxypyranone, and catechol moieties have been synthesized in order to investigate their potential as clinically useful iron(III)-selective chelators capable of removing dietary iron from the gastrointestinal tract and preventing the development of iron overload typical of haemochromatosis and thalassaemia intermedia. The iron chelating abilities of these molecules have been characterized by MALDI-TOF mass spectrometry and UV spectrometry. Hydroxypyridinone-terminated dendrimers were found to possess a high affinity and selectivity for iron(III). A hydroxypyridinone-based dendrimer was demonstrated to be highly efficient at reducing the absorption of iron(III) in rat intestine. This family of dendrimers may find an application in the treatment of iron overload.

Iron is essential for the proper functioning of all living cells, however it is toxic when present in excess. Thus, using iron chelators as therapeutic agents, namely chelation therapy, has received increasing attention. The objective of this review is to discuss the factors which should be considered when designing clinically useful iron chelators, to present the application of iron chelators in the treatment of iron overload associated with β-thalassaemia major and sickle cell anaemia, and to highlight the potential applications in the treatment of neurodegenerative disorders and microbial infection. This article reviews recent knowledge centred on these themes and indicates the growing importance of the concept of iron chelation in medicine.

The nature of the cytosolic iron pool remains largely uncharacterized, although a range of candidate ligands and chaperones have been proposed. Herein an overview is presented of cytosolic non heme and non iron-sulphur cluster protein iron binding sites and the influence of ligands on the redox activity of iron. This analysis leads to the concept of iron(II) glutathione functioning as the labile cytosolic iron pool and offers a means for the selection of iron over manganese in subsequent incorporation into a wide range of iron-dependent enzymes and electron transfer proteins. Glutathione and glutathione-binding glutaredoxins play a critical role in iron sulfur cluster synthesis and Fe(II)GS (iron(II) coordinated by the thiol function of glutathione) is a suitable iron donor for this biosynthetic route. Significantly, both glutathione and glutaredoxins are universally distributed and thus a controlling influence of glutathione on intracellular iron trafficking is likely to be a common feature of the majority of living organisms.