Ferrichromes and ferrioxamines

The stability constants of the FeIU siderophore complexes are some of the largest known, e.g. the ferrichrome and ferrioxamine E complexes have log values of the order 29 and 32 respectively as compared to a value of 25 for Fe(edta). So strong are these complexes that microbes have been observed to leach iron from stainless steel vessels. Not surprisingly the siderophores also find use in treating cases of iron poisoning and for the elimination of iron from cases of thalassaemia.84 Complexation of Fe11 is considerably weaker than that of FeIU and this is probably utilized for the release of the iron within the cells. 

As mentioned above, transport of siderophores across the cytoplasmic membrane is less specific than the translocation through the outer membrane. In E. coli three different outer membrane proteins (among them FepA the receptor for enterobactin produced by most E. coli strains) recognise siderophores of the catechol type (enterobactin and structurally related compounds), while only one ABC system is needed for the passage into the cytosol. Likewise, OM receptors FhuA, FhuE, and Iut are needed to transport a number of different ferric hydroxamates, whereas the FhuBCD proteins accept a variety of hydroxamate type ligands such as albomycin, ferrichrome, coprogen, aerobactin, shizokinen, rhodotorulic acid, and ferrioxamine B [165,171], For the vast majority of systems, the substrate specificity has not been elucidated, but it can be assumed that many siderophore ABC permeases might be able to transport several different but structurally related substrates. 

Figure 10 A schematic drawing of the cell envelope of E. coli consisting of the cytoplasmic membrane, the periplasm, and the outer membrane. Various proteins are shown, sets of which represent specific siderophore-transport systems. Outer-membrane receptors (OMR) shown here are FepA (enterobactin), lutA (aerobactin), Fee A (Fe dicitrate), FhuA (ferrichrome), and FhuE (coprogen, Fe rhodotorulate, and ferrioxamine B). FoxA (ferrioxamine B), is not a receptor of E.coli, but of the closely related Salmonella. Not shown here are the receptors Fiu and Cir (Fe (DHBS) n indicates 3 possible linear degradation products of enterobactin) and FeO, a transport system for Fe . Details are discussed in Section 5.1...

The ferrichromes, fusarinines, and ferrioxamines are typical trihydroxamate siderophores, while enterobactin is a cyclic tricatecholate siderophore. However, there are several exceptions which employ mixed forms of coordination. For example, aero-bactin, schizokinen and arthrobactin contain, in addition to two hydroxamate groups, a a-hydroxy-carboxylate unit which completes the hexadentate ligand structure 30). The recently isolated ferrioxamine H, with two hydroxamate and one carboxylate, is only pentadentate — the sixth coordination site presumably occupied by water 31). 

The conformational studies on the ferrichromes and on ferrioxamine B indicate that a number of intramolecular hydrogen bonds are formed in the process of metal-chelation and that these contribute to the overall stability of the coordinated conformation relative to that of the free species. Consistent with this view, it should be mentioned that extensive hydrogen bonding has also been observed in the low molecular weight monovalent cation complexes of the antibiotics monensin, nigericin, dianemycin, the enniatins and valinomycin by NMR spectroscopy (69, 70), X-ray crystallography (71, 72, 73), or both. Like the siderochromes, these compounds act by mediating cation fluxes across membranes. 

Fig. 19. Plot of redox potentials (Ey2) as a function of pFe3+ values for a series of hexadentate, tetradentate, and bidentate hydroxamic acid siderophores and siderophore mimics. Data from Table V. Legend 1 — ferrioxamine E 2 — ferrioxamine B (4) 3 — H.aLjf4 (11) 4 — H >L 36 (12) 5 - coprogen 6 - ferricrocin 7 - ferrichrome (6) 8 - alcaligin 9 -rhodotorulic acid (3) 10 — NMAHA 11 — AHA 12 — Ly-AHA.

In accordance with Emery s retro-hydroxamate ferrichrome, mentioned above, two retro analogs of the linear ferrioxamine G and cyclic desferrioxamine E (129 and 130, respectively) were prepared. The iron-chelating properties were compared to DFO, showing that the linear retro-desferrioxamine G (131) binds iron faster and the cyclic retro desferrioxamine E (132) has improved affinity to iron, compared to the linear DFO. Based on these resnlts, many retro-hydroxamate ferrioxamines were prepared. In a later paper, Akiyama and coworkers reported the attachment of -cyclodextrin, a cyclic oligosaccharide, composed of seven a-D-glucopyranoside units, linked from position 1 to position 4, to linear retro-hydroxamate ferrioxamines (133 and 134), which formed 1 1 iron(III) complexes. Influenced by the chiral -cyclodextrin gronp, 133 and 134 formed A-selective coordination around the metal ion. In addition, Akiyama proposed that the... 

Two fluorescent siderophore analogs, one based on ferrichrome 173 and the second on ferrioxamine 188, were used to study iron transport in the fungus Ustilago maydis that has an uptake system for ferrichrome but lacks a defined ferrioxamine receptor. Nevertheless, ferrioxamine can be utilized by the fungus albeit at a slower rate. 

Exchange of iron between ferrioxamine B and ferrichrome A at pH 7.4 has a half-life of about 220 h.1196... 

However, despite large differences in ligand molecular structure, all of the hydroxamate siderophores whose structures have been determined to date have been found to be cis complexes with a coordination geometry about the ferric ion which is substantially identical to the simple tris-(benzhydroxamato)-Fe(III) complex. Thus, while ferrioxamine E is racemic but with a cis geometry (13), x-ray structure analyses of ferrichrome A (14) and ferrichrysin (15) have shown both to be A-cis isomers. 

The second main class of Fem-specific sequestering agents (siderophores) responsible for the acquisition and assimilation of iron employ hydroxamate ligating groups (34).157158 186 Two important subclasses are the ferrioxamines and the ferrichromes (Figure 5). Examples are ferrioxamine B, a linear trihydroxamic acid and ferrichrome A, a cyclic hexapeptide carrying three hydroxamate-containing side chains. 

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