Siderophores iron release

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... 

One aspect of microbial iron metabolism that remains unclear in many cases is the mechanism for iron release from tight sequestration once the siderophore complex arrives at its... 

Another possible route for reduction of the iron center is photoreduction. This has been studied in a variety of marine siderophore systems, such as aquachelin, marinobactin, and aerobactin (2), where it was demonstrated that photolytic reduction was due to a ligand-to-metal charge transfer band of the Fe(III)-siderophore complex, eventually resulting in reduction ofiron(III) and cleavage of the siderophore (31,154,155). This suggests a possible role for iron reduction in iron release (71,155). 

Once the siderophore-iron complexes are inside the bacteria, the iron is released and utilized for vital cell functions. The iron-free hydroxamate siderophores are commonly re-excreted to bring in an additional iron load (Enterobactin is at least partially degraded by a cytoplasmic esterase This cycle is repeated until specific intracellular ferric uptake regulation proteins (Fur proteins) bind iron, and signal that the intracellular iron level is satisfactory, at -which point ne-w siderophore and siderophore-receptor biosynthesis are halted and the iron-uptake process stops. This intricate feedback mechanism allows a meticulous control over iron(III) uptake and accumulation against an unfavorable concentration gradient so as to maintain the intracellular iron(III) level within the required narrow window. Several excellent reviews concerning siderophore-iron transport mechanisms have been recently published i.3,i6, is,40,45,60-62 ... 

W(VI) centers. At room temperature and under mild conditions, iron release from the complexes is observed upon reduction of the Fe(III) centers. This release is controlled by the ionic strength of the medium, the nature and concentration of the anions present in the supporting electrolyte, and by the pH of the solution. This behavior parallels those described for most siderophores that depend on the same parameters. 

Investigations of the kinetics of the reaction of these new siderophores with iron-saturated transferrin showed a rapid formation of a ternary complex with transferrin, followed by a slow step in which the ferric siderophore was released from the apoprotein. Weitl et al.257 have evaluated the ferric-chelating properties of several of these siderophores and found the following order of effectiveness for removing iron from transferrin enterobactin > MECAMS > MECAM > LICAMS > DFOA > TRIM-CAMS. 

In times of iron deficiency, many bacteria and fungi release low molecular weight chelators called siderophores (see Iron Transport Siderophores). These molecules bind ferric iron tightly and the ferric-siderophore complexes are then transported into the cell by a system of uptake proteins. The first stage in the uptake process involves an outer membrane receptor specific to each siderophore. One of the best characterized of these receptors is FhuA, the ferrichrome uptake receptor of E. coli, and we will describe this in detail. However, though other ferric-siderophore complexes are taken up by cells, and their iron released by systems similar to those of ferrichrome, their mechanisms may vary from those of ferrichrome in some respects. FepA and FecA" are two of the outer membrane ferric-siderophore receptors that have recently been structurally characterized. 

N, 6-N-di(2,3-dihydroxybenzoyl)-L-lysine (58) is a siderophore produced by Azotobacter vinelandii which has only two catechol groups. However, of the catecholate siderophores by far the best studied is enterobactin. A major difference between hydroxamate and catecholate siderophores occurs in their utilization as transport agents. For the former, the iron complex is taken up by the bacterial cell, the iron released, and the hydroxamate siderophore re-secreted for additional iron chelation. In contrast, enterobactin is destroyed by enzymatic hydrolysis within the cell and therefore the ligand is not recycled. This hydrolysis of the amide linkages of the iron(III) enterobactin lowers the redox potential of the chelate complex sufficiently to allow iron reduction — and thus uptake of iron into the cell metabolism (59, 60). 

Although the redox potential of FhuF is in the same range as NADH, FhuF is capable of reducing ferrioxamine B (see Table 4) in vitro and in vivo. In fact, it has been postulated that it is the redox potential of the ternary reductase-ferric-siderophore complex rather than the redox potential of the free ferric siderophore that is important when considering reduction as a process involved in iron release. In general, one has to bear in mind that a thermodynamically unfavorable process can nevertheless be driven if steady-state conditions are applied. In addition, the pH could influence the redox potential of a siderophore. For example, the midpoint potential of ferrioxamine B is —468 mV at pH 7.4, but increases to -180 mV at pH 4.5.i ... 

In addition to being an indirect measurement of the formation constant (Ki) of the iron complex, the reduction potential of the ferric siderophore complex is an important factor in developing the iron-release mechanism for siderophore-mediated iron transport. Under standard conditions, the reduction potentials for most known siderophores (ferric enterobactin —750 mV NHE V" ferriferrioxamine B 450mV NHE ) seem to preclude the use of biological reduc-tants (NAD(P)H/NAD(P)+ —324mV NHE ) to reduce the ferric ion to the ferrous ion and therefore prompt release of the ion from the siderophore. However, this potential is highly sensitive to the ratio of [Fe +]/[Fe +], as predicted by the Nernst equation. 

Transition-metal complexes of a-hydroxy acids can be photolabile. The oil-degrading marine bacterium Marinobacter hydrocarbonoclasticus produces a siderophore, which appears to exploit photodecarboxylation to facilitate iron release. Petrobactin (Figure 4) forms a stable ferric complex through iron chelation by two catecholate moieties and a citryl group. Decarboxylation of the citryl moiety via photolysis of ferric petrobactin yields a less stable ferric complex than the... 

Iron(III) complexes of hexadentate siderophores are kinetically and thermodynamically stable, which although being ideal for their scavenging roles, presents problems to the organism with respect to iron release. Redox pro-... 

A Figure 24.17 The iron-transport system of a bacterial cell. The iron-binding ligand, called a siderophore, is synthesized inside the cell and excreted into the surrounding medium. It reacts with Fe ion to form ferrichrome, which is then absorbed by the cell. Inside the cell the ferrichrome is reduced, forming Fe ", which is not tightly bound by the siderophore. Having released the iron for use in the cell, the siderophore may be recycled back into the medium. 

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