Ferrioxamines

Mikes and Turkova have given a classification of naturally occurring hydroxamic acids in terms of their biological function or activity. They have distinguished (a) growth factors, e.g., ferri-chromes, mycobactin, and ferrioxamines, ferrichrysins, ferrirubins, etc. (6) antibiotics, e.g, aspergillic acid, mycelianamide, albomycin, nocardamine and (c) microbial pigments such as pulcherrimin. 

The ferrioxamines form a large group of ferric trihydroxamates composed of residues of acetic acid, succinic acid, l-amino-5-hydroxyl-aminopentane, and l-amino-4-hydroxylaminobutane. Of the.se, only ferrioxamines E (14) and D2 (15) are formally cyclic hydroxamic acids. 

The use of microbial siderophores by dicotyledonous plants appears to involve uptake of the entire metallated chelate (42-44), or an indirect process in which the siderophore undergoes degradation to release iron (45). As demonstrated in initial studies examining this question, there was concern that iron uptake from microbial siderophores may be an artifact of microbial iron uptake in which radiolabeled iron is accumulated by root-colonizing microorganisms (46). Consequently, evidence for direct uptake of iron from microbial siderophores has required the use of axenic plants. In experiments with cucumber, it was shown that the microbial siderophore ferrioxamine B could be used as an iron source at concentrations as low as 5 pM and that the siderophore itself entered the plant (42). 

The po.ssible role of a chelate reductase for iron uptake from microbial siderophores has been examined for several plant species (30,47). With certain microbial siderophores such as rhizoferrin and rhodotorulic acid, the reductase may easily cleave iron from the siderophore to allow subsequent uptake by the ferrous iron transporter. However, with the hydroxamate siderophore, ferrioxamine B, which is produced by actinomycetes and u.sed by diverse bacteria and fungi, it has been shown that the iron stress-regulated reductase is not capable... 

Y. Wang, H. N. Brown, D. E. Crowley, and P. J. Szaniszlo, Evidence for direct utilization of a siderophore, ferrioxamine B in axenically grown cucumber Plant Cell Environ. 76 579 (1993). 

E. Bar Ness, Y. Hadar, Y. Chen, and A. Shanzer, Iron uptake by plants from microbial siderophores—a study with 7 nitrobenz-2oxa-1,3-diazole desferrioxamine as fluorescent ferrioxamine B analog. Plant Physiol. 99 1329 (1992). 

Ferrioxamines Hydroxamic acid 3 Species of Nocardia, Micromon-ospora, Streptomyces, and Actinomyces... 

Siderophores are iron-complexing compounds of low molecular weight that are synthesized by bacteria and fungi, and serve to deliver iron to the microbes. Because of their exclusive affinity and specificity for Fe3+, natural siderophores and synthetic derivatives have been exploited in the treatment of human iron-overload diseases. The most successfully used example is Desferal , which is the methane sulfonate derivative of iron-free ferrioxamine B, a linear trihydroxamate (Figure 3.2). Ferrioxamine was isolated in 1958 from the culture supernatant of Streptomyces... 

Staphylococcus aureus Not applicable FhuB, FhuG FhuC Ferrioxamine Sebulsky et ah, 2000... 

S.R. Smith and H.H. Thorp, Application of the electrocatalytic reduction of nitric oxide mediated by ferrioxamine B to the determination of nitric oxide concentrations in solution. Inorg. Chim. Acta 273, 316-319(1998). 

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.

Fig. 24. Stepwise process for H+-assisted dechelation of iron from ferrioxamine B.

Fig. 27. Stereochemistry observed for ferrioxamine B resulting in a carbonyl face for the inner coordination shell of Fe(III) that may play a role in recognition. Legend dark grey = O atom light grey = N atom black = Fe atom white = C atom. Figure based on X-ray crystal structure and adapted from Fig. 4b in Ref. (195) and used with kind permission of Springer Science Business Media.

Siderophore-ionophore supramolecular assembly formation via host-guest complexation of the pendant protonated amine arm of ferrioxamine B has been confirmed by X-ray crystallography (Fig. 28) (203). The stability and selectivity of this interaction as a function of ionophore structure, metal ion identity, and counter anion identity were determined by liquid-liquid extraction, isothermal calorimetry, and MS (204 -211). Second-sphere host-guest complexation constants fall in the range 103— 106M-1 in CHC13 and methanol depending on ionophore structure. 

Second coordination shell complexation of hydrophilic ferrioxamine B produces a hydrophobic supramolecular siderophore-ionophore assembly. The hydrophobic characteristic in concert... 

Fig. 28. Host-guest complex formed between ferrioxamine B (4) and 18-crown-6 crown ether an ionophore-siderophore supramolecular assembly.

BLM transport systems for ferrioxamine B were also devised based on first coordination shell recognition via ternary complex formation utilizing vacant coordination sites on the Fe(III) center (Fig. 29) (199). The tetra-coordinated substrate complex selectively transported was partially dechelated diaqua-ferrioxamine B and coordinately unsaturated di-hydroxamato iron(III) complexes, which utilized a hydrophobic membrane bound bidentate chelator as a carrier for selective transport. Active transport for these systems was accomplished using a pH gradient (199). 

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. 

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