Fe3+, siderophores

FhuA and FepA will prove to be the reference structures for a large group of bacterial outer-membrane transporters that take up bacterial Fe3+-siderophores, Fe3+ released from host transferrin and lactoferrin, haem, and haem released from haemoglobin and haemopexin. It is assumed that all iron sources are transported... 

There are other mechanisms by which Fe3+ siderophores induce the formation of their cognate transport systems. The reader is referred to recent reviews (Crosa, 1997 Vasil and Ochsner, 1999 Venturi et ah, 1995). 

Fig. 21. Redox potentials (Ey2) of Fe3+ siderophore and siderophore mimic complexes as a function of pH. Lines represents a fit of Eq. (41) to the data, which are taken from Refs. (3,58,59,91). Adapted with permission from Ref. (4).

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... 

Figure 3.2 Chemical structures of selected siderophores to demonstrate the four major structural classes and the different solutions of microorganisms to scavenge iron. See for comparison the conformations of the Fe3+-complexes of ferrichrome and albomycin shown in Figure 3.5.

While much is known about siderophore-mediated ferric-iron transport, very little is known about ferrous-iron transport and iron metabolism inside the cell. It is generally assumed that Fe3+ chelated to the siderophore must be reduced to allow removal from the strong claws of the chelator. Indeed, in some cases the siderophore transported iron was found 30 minutes later in the intracellular Fe2+ pool of the cells (Matzanke et ah, 1991). 

Siderophore binding sites for iron(III) are for the most part negatively charged and therefore, in aqueous solution there is a competition between H+ and Fe3+ binding. Consequently, the equilibrium expression for the formation of the iron-siderophore complex must take into account proton participation in the reaction. 

This means that the sequestration equilibrium reaction will be pH-dependent. The constant K is known as the conditional equilibrium constant. However, for stability comparisons between complexes of the same denticity, it may be more convenient to compare the equilibrium constant for the proton independent reaction between iron and siderophore. This can also be useful in a theoretical sense, as it allows comparison of complex stability where siderophores have different protonation constants. However, this approach does not account for competition between H+ and Fe3+ for binding, which is always present in a real situation in aqueous solution. 

Stability comparisons between siderophore complexes with different binding stoichiometries are complicated by the fact that the units for the concentration equilibrium constants are different. Also, since the Fe3+ binding moieties have different pKa values competition for binding with H+ differs, which will not be reflected in the pH-independent / mlh values. Therefore, it is important to have a scale for iron-siderophore complex... 

These pFe values were calculated for [Fe3+]tot = 10 M, [L]t = 10 2M, and pH = 7.4. Tleteropodal hexadentate siderophore mimics with various binding groups. 

Formal Fe3+/Fe2+ Redox Potentials for Ferri-Siderophore and Siderophore Mimic Complexes at Potential-Limiting, High-pH Conditions... 

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). 

Some bacteria possess uptake systems of all the ABC types mentioned in this chapter. For example, the pathogenic microbe H. influenzae is able to sequester iron via siderophore-type systems, ferric iron systems, and metal-type systems. Similarly, strains of Yersinia use multiple routes to take up iron bound to siderophores (e.g. yersiniabactin) and haem, as well as unliganded iron by the ferric-iron-type Yfu system and the metal-type Yfe system. No iron-uptake systems of the ABC transporter type were identified in the genomes of Mycoplasma genitalium and Mycoplasma pneumoniae. In contrast, among the 19 ABC transporters of the related species Ureaplasma urealyticum six presumed different Fe3+ and/or haem transporters were identified [228]. 

Siderophores. If a suitably high content of iron (e.g., 50 pM or more for E. coli) is maintained in the external medium, bacteria and other microorganisms have little problem with uptake of iron. However, when the external iron concentration is low, special compounds called siderophores are utilized to render the iron more soluble.7 11 For example, at iron concentrations below 2 pM, E. coli and other enterobacteria secrete large amounts of enterobactin (Fig. 16-1). The stable Fe3+-enterobactin complex is taken up by a transport system that involves receptors on the outer bacterial membrane.9 12 13 Siderophores from many bacteria have in common with enterobactin the presence of catechol (orftzo-dihydroxybenzene) groups... 

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