Siderophore chelate effect

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). 

Another factor that can possibly affect the redox potential in biological systems is the presence of secondary chelating agents that can participate in coupled equilibria (3). When other chelators are present, coupled equilibria involving iron-siderophore redox occur and a secondary ligand will cause the siderophore complex effective redox potential to shift. The decrease in stability of the iron-siderophore complex upon reduction results in a more facile release of the iron. Upon release, the iron(II) is available for complexation by the secondary ligand, which results in a corresponding shift in the redox equilibrium toward production of iron(II). In cases where iron(II) is stabilized by the secondary chelators, there is a shift in the redox potential to more positive values, as shown in Eqs. (42)—(45). 

Sickle cell disease 16, 359, 360 Side chains packing 75 Siderophilins 840 Siderophore(s) 838, 838s chelate effect 310 receptors 839 Sieve plates 30 Signal peptidase 522, 620 Signal recognition particle (SRP) 520 Signal sequences 519 Signaling 1... 

Fig. 2.1 Chelate effects in high affinity artificial complexes (1) an artificial siderophore with K =l0 M (2) a ionophore binding Cs" ions in chloroform with AC = 90 kj/mol (3) an azacrown ether and triphosphate residue (as in ATP) as guest, with /f=10" M" (only 7 out of the possible 10 to 12 charge-charge...

As mentioned previously, siderophores must selectively bind iron tightly in order to solubilize the metal ion and prevent hydrolysis, as well as effectively compete with other chelators in the system. The following discussion will address in more detail the effect of siderophore structure on the thermodynamics of iron binding, as well as different methods for measuring and comparing iron-siderophore complex stability. The redox potentials of the ferri-siderophore complexes will also be addressed, as ferri-siderophore reduction may be important in the iron uptake process in biological systems. 

As mentioned previously, in many siderophore complexes, a decrease in pH will result in protonation and dissociation of a donor group. This decrease in effective denticity of the chelator will lead to a corresponding decrease in complex stability and the opening of available coordination sites for the formation of ternary complexes, and/or exchange with other chelators. However, in the case of catecholamide donor group siderophores, such... 

Chelators of iron, which are now widely applied for the treatment of patients with thalassemia and other pathologies associated with iron overload, are the intravenous chelator desferal (desferrioxamine) and oral chelator deferiprone (LI) (Figure 19.23, see also Chapter 31). Desferrioxamine (DFO) belongs to a class of natural compounds called siderophores produced by microorganisms. The antioxidant activity of DFO has been studied and compared with that of synthetic hydroxypyrid-4-nones (LI) and classic antioxidants (vitamin E). It is known that chronic iron overload in humans is associated with hepatocellular damage. Therefore, Morel et al. [370] studied the antioxidant effects of DFO, another siderophore pyoverdin, and hydroxypyrid-4-ones on lipid peroxidation in primary hepatocyte culture. These authors found that the efficacy of chelators to inhibit iron-stimulated lipid peroxidation in hepatocytes decreased in the range of DFO > hydroxypyrid-4-ones > pyoverdin. It seems that other siderophores are also less effective inhibitors of lipid peroxidation than DFO [371],... 

Polycarbonyl and polyamino compounds include chelates, which are manmade compounds, and siderophores, which are biologically derived and more specialized. They can help dissolve inorganic ions, keep ions in one specific ionic state, and maintain them in biologically available forms. Because of their ability to bring ions into solution, they are often used to extract specific ions in specific forms from soil. Cationic micronutrients, particularly iron and zinc, are often applied in chelated form as a foliar spray to alleviate nutrient deficiencies. This is particularly true of plants growing in basic soil and is done even when plants do not show micronutrient deficiencies. Typically, both foliar and soil applications are effective in this regard. 

Experiments performed in vitro revealed that in contrast to DFO, which has a major cytotoxic effect only on trophozoites and early schizonts of P. falciparum, reversed siderophores have a cytotoxic effect on ring-stage and cytostatic effects on trophozoites and schizonts . These observations provided the basis for studying combinations of iron chelators for antimalarial therapy. When DFO is added to malaria parasites cultured in erythrocytes in combination with the more lipophilic and more permeate reversed siderophore 66, a strong synergistic inhibitory effect on parasite growth is observed. This effect may result from the different speeds of permeation of the two chelators... 

Microbes acquire iron by utilizing very specific, low molecular weight iron chelators called siderophores. The resistance of bacteria to previously effective antibiotics can be circumvented in part by covalent coupling of antibiotics to siderophores. Some synthetic siderophores have been found to possess significant antibacterial activity themselves. They have also been found to have considerable potential as nontoxic, organ selective MRI contrast agents (27). 

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. 

The biomimetic approach to the synthesis of new siderophores has not been restricted to studies in the USA Kontoghiorghes241 242,269) has synthesized hydroxypyridones (34, 35) and demonstrated their ability to mobilize iron(III) from ferritin. Intragastric administration of l,2-dimethyl-3-hydroxy-pyrid-4-one (34) proved to be as effective as intramuscular DFOA in mobilizing iron from the iron-overloaded rat. This effectiveness of an orally administered chelating agent is particularly noteworthy. 

---