Structure natural siderophores

The only clinically approved and therefore most studied natural siderophore is des-ferrioxamine B (DFO), and hence it serves as a reference compound in evaluating new biomimetic siderophores. The following discussion will include a short description of several natural hydroxamate siderophore families in separate tables, followed by the various attempts to prepare novel simplified structures that reproduce biological activity. These tables are not intended to cover the entire archive of known siderophores, but merely to allow the reader to observe structural variations, their chemical composition and location as well as conserved domains. 

Albomycins, natural siderophores and antibiotics first isolated from Streptomyces griseus and named grisein in 1947. Some years later, another microbial iron-transport compound, named albomycin, was isolated from Streptomyces subtropicus which had the same structure as grisein. In 1982, the structure of the albomycins was firmly established. The linear tripeptide built of N -acetyl-N -hydroxy-L-omithine is the hexadentate, octahedral ligand for ferric ion responsible for intraceUular transport of iron. The albomycins are used for treatment of iron metabolism disorders [G. Benz et al., Angew. Chem. Int. Ed. 1982, 21, 527 G. Benz, Liebigs Ann. Chem. 1984, 1408]. 

In continuation of their research on N-hydroxypeptides Akiyama s group obtained the anilide hexapeptide with a 6-aminohexanoyl-3-(hydroxyamino)propanoyl sequence (225). This linear tri-N-hydroxy-amide bears a structural resemblance to the natural siderophores fer-rioxamines. Cyclic voltametry and UV spectrometry were used for the study of its iron complex. The key substrate was obtained by the addition of benzyloxyamine to / -nitrophenyl acrylate. 

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). 

The NMR structure of the 37 kDa PCP-TE didomain construct from the E. coli enterobactin NRPS synthetase provides a detailed picture of the functional interactions between these two domains. As described in Section 5.19.5, the enterobactin TE works with the adjacent PCP domain to catalyze a trimerization/cyclization of 2,3-dihydroxybenzyl serine to generate the siderophore natural product (see Figure 4(b)). NMR analysis... 

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. 

Structural work may take its time. Examples are Pseudomonas mendocina (Sect. 2.9) where the first structural data were reported in 2000 and the next pertinent publication appeared in 2008, or Legionella pneumophila (Sect. 4.5) whose legiobactin was first characterized in 2000, further details followed in 2007 and 2009, with loose ends in both cases. Only partially characterized siderophores are mentioned wherever data were available in order to stimulate further work. This would be worthwhile siderophore research is a fascinating branch of natural products chemistry promising sometimes surprising results e.g. 311, 388)). 

Demange P, Bateman A, Mertz C, Dell A, Piemont Y, Abdallah MA (1990) Bacterial Siderophores Structure of Pyoverdins Pt, Siderophores of Pseudomonas tolaasii NCPPB 2192, and Pyoverdins Pf, Siderophores of Pseudomonas fluorescens CCM 2798. Identification of an Unusual Natural Amino Acid. Biochemistry 29 11041... 

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. 

Natural and biomimetic hydroxamic acid based siderophores TABLE 2. Natural ferrioxamines and their structural variations... 

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 obvious method of choice is to model novel structures on natural hydroxamate and catechol siderophores which possess extremely high affinities for iron(III) [35], Hydroxamates possess many advantages for iron(III) chelation, as was outlined in the section on bidentate ligands. However, they tend to possess a low oral activity. Nevertheless, a number have been investigated, including rhodotorulic acid [36], synthetic hexadentate [37] and polymeric hydroxamates [38]. None has proved superior to DFO (Structure 2, Scheme IB). 

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