Natural siderophores ferrichromes

Siderophores,hexadentate tris-catecholate and tris-hydroxamate ligands, are produced by many microorganisms to facihtate iron uptake. Several synthetic models, such as trencam (35) and licams (36), for the tris-catecholate enterobactin (37) do not quite match its affinity for iron(ni) (Table 8). Similar tris-hydroxamate ligands model naturally occurring ferrichromes and desferrioxamines (e g. dfo, (38)). 

Figure 6.18. MacrcKyclic complex fonners. (a) Structure of a ferrichrome (desferri-ferrichrome), one of the strongest complex formers presently known for Fe(III). The iron-binding center is an octahedral arrangement of six oxygen donor atoms of trihy-droxamate. Such naturally occurring ferrichromes play an important role in the biosynthetic pathways involving iron. Complexing functionalities of some biogenic ligands (b) hydroxamate siderophores, (c) catechol siderophores, and (d) phytochelatines. For detailed structures see Neilands (1981).

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). 

Relationships between the structure of the siderophores and the iron transport were investigated for the fungus Neurospora crassa (160, 160a). Apparently two different receptors exist for ferrichromes and for coprogenes. For the recognition and the binding to the cell surface the iron configuration and the nature of the acyl chains is of importance. However, the transport system seems to be the same for both siderophore types dependent on the peptide part of the molecules. 

The closely related structures show completely different microbial uptake characteristics. The 3D structures described above show distinct different orientation of the backbone amide (tangental in type 1 versus radial in type 2), which can be explained by the interactions that take place between the FhuA receptor and the ferrichrome siderophore -As mentioned, the second coordination sphere of natural ferrichrome in FhuA receptor is very sensitive to the distance and orientation between a proton donor and the proton acceptor, therefore the orientation of the amide groups in the biomimetic siderophore plays a crucial role in receptor recognition. 

Figure 2. Crystal and solution structure of the ferrichrome siderophores as determined by x-ray diffraction (11) and high resolution NMR (12). The ferrichrome peptides differ in the nature of the acyl substituent at the metal hydroxamate (R) and in the side chains of the three small, neutral, spacer amino acids (R1, R2, and R3). Ferrichrome M = Fe R = CHa R R2 = R3 = H (see also Figure 6 and Refs.

The first synthesis of a siderophore was the preparation of ferrioxamine B over 20 years ago in order to confirm the chemical structure of this natural product67). Synthesis of the other hydroxamate containing siderophores has as a central problem preparation of the constituent to-N-hydroxy amino acid in an optically pure form. The most important such subunit in hydroxamate siderophores is Ns-hydroxy ornithine. This is a chiral building block of the diketopiperazine-containing siderophores (rhodo-torulic acid 68), dimerum acid 69), coprogen 70) and coprogen B 69>), the cyclic hexa-peptides of the ferrichrome family27), the fusarinines 71 -73) and the antibiotic ferri-chrome derivatives albomycines Sl5 S2 and e 61-62). 

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