Hydroxamate siderophores

Fe(III) displacement of Al(III), Ga(III), or In(III) from their respective complexes with these tripodal ligands, have been determined. The M(III)-by-Fe(III) displacement processes are controlled by the ease of dissociation of Al(III), Ga(III), or In(III) Fe(III) may in turn be displaced from these complexes by edta (removal from the two non-equivalent sites gives rise to an appropriate kinetic pattern) (343). Kinetics and mechanism of a catalytic chloride ion effect on the dissociation of model siderophore-hydroxamate iron(III) complexes chloride and, to lesser extents, bromide and nitrate, catalyze ligand dissociation through transient coordination of the added anion to the iron (344). A catechol derivative of desferrioxamine has been found to remove iron from transferrin about 100 times faster than desferrioxamine itself it forms a significantly more stable product with Fe3+ (345). 

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... 

Hydroxamic acids constitute an important class of siderophores, which play a major role in iron solubilization and transport. Some of them are important as therapeutic agents. The Michael addition of nitroacetyl proline esters to allyl acrylate followed by Pd(0)-catalyzed intramolecular allyl transfer and subsequent reduction of the nitro group yields a novel class of cyclic hydroxamic acids related to pyroglutamic acid (Scheme 5.9).85... 

There is some evidence that the iron-sulfur protein, FhuF, participates in the mobilization of iron from hydroxamate siderophores in E. coli (Muller et ah, 1998 Hantke, K. unpublished observations). However, a reductase activity of FhuF has not been demonstrated. Many siderophore-iron reductases have been shown to be active in vitro and some have been purified. The characterization of these reductases has revealed them to be flavin reductases which obtain the electrons for flavin reduction from NAD(P)H, and whose main functions are in areas other than reduction of ferric iron (e.g. flavin reductase Fre, sulfite reductase). To date, no specialized siderophore-iron reductases have been identified. It has been suggested that the reduced flavins from flavin oxidoreductases are the electron donors for ferric iron reduction (Fontecave et ah, 1994). Recently it has been shown, after a fruitless search for a reducing enzyme, that reduction of Co3+ in cobalamin is achieved by reduced flavin. Also in this case it was suggested that cobalamins and corrinoids are reduced in vivo by flavins which may be generated by the flavin... 

Fig. 1. Common siderophore iron-binding groups catechol (Eq. (4)), hydroxamic acid (Eq. (5)), ot-hydroxycarboxylic acid (Eq. (6)), and hydroxypyridinone (Eq. (7)). Additional siderophore binding groups ...

Another factor that relates complex stability and siderophore architecture is the chelate effect. The chelate effect is represented by an increase in complex stability for a multidentate ligand when compared to complexes with homologous donor atoms of lower denticity. The effect can be observed when comparing the stability of complexes of mono-hydroxamate ligands to their tris-hydroxamate analogs, such as ferrichrome (6) or desferrioxamine B (4). However, the increase in stability alone is not sufficient to explain the preponderance of hexadentate siderophores over tetradentate or bidentate siderophores in nature, and the chelate effect is not observed to a great extent in some siderophore structures (10,22,50,51). 

Fig. 6. Saccharide-platform siderophore mimics with catechol and hydroxamic acid donor groups, H6L 34(9), H6Lg34(10), H3L 34(11), and H3L236(12).

Another study of a synthetic siderophore analog of mixed cathechol and hydroxamate donor groups exhibited similar spectral shifts with pH as observed for tris-catecholate side-rophores, consistent with a salicylate-binding mode shift (102). While this synthetic siderophore mimic supports the growth of many species of bacteria, it also exhibits a low iron-binding affinity relative to other hexadentate siderophores, with a pFe value of 18.3 (see L(cat2hydroxamate) Table HE). 

In addition to structure, the dihydroxamate connecting chain length will affect the affinity of linear siderophores and side-rophore mimics for iron(III) (Table IIIA). If the chain connecting the hydroxamates is long, there will be a significant entropic... 

Another factor that will affect the complex redox potential is the architecture of the siderophore. A plot of ferri-siderophore redox potentials as a function of pFe for a series of hydroxamate complexes of differing denticity (shown in Fig. 19) exhibits a trend. The trend demonstrates that hydroxamate siderophores of higher denticity will form complexes with more negative E1/2 values than analogous siderophores of lower denticity. 

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.

Matsumoto et al. demonstrated that the removal of iron from diferric transferrin by the tris-hydroxamate siderophore mimic TAGE occurs in two discreet steps (90). The slower step corresponds to iron removal from the more stable C-lobe site on transferrin and the faster step to removal from the N-lobe. The rates of removal are similar to the rates of removal of iron from diferric transferrin by desferrioxamine B (4), signifying similar mechanisms of removal between the two systems (90). 

---