Hydroxamates ferrichromes

On the other hand, desmethyl-retro-hydroxamate ferrichrome 15, where the terminal methyl groups were replaced by hydrogen, showed no signihcant growth promotion activity toward Arthrobacter flavescence, and only one third of the iron(III) transport efficiency toward U. sphaerogena, which confirms the importance of the methyl groups... 

In accordance with Emery s retro-hydroxamate ferrichrome, mentioned above, two retro analogs of the linear ferrioxamine G and cyclic desferrioxamine E (129 and 130, respectively) were prepared. The iron-chelating properties were compared to DFO, showing that the linear retro-desferrioxamine G (131) binds iron faster and the cyclic retro desferrioxamine E (132) has improved affinity to iron, compared to the linear DFO. Based on these resnlts, many retro-hydroxamate ferrioxamines were prepared. In a later paper, Akiyama and coworkers reported the attachment of -cyclodextrin, a cyclic oligosaccharide, composed of seven a-D-glucopyranoside units, linked from position 1 to position 4, to linear retro-hydroxamate ferrioxamines (133 and 134), which formed 1 1 iron(III) complexes. Influenced by the chiral -cyclodextrin gronp, 133 and 134 formed A-selective coordination around the metal ion. In addition, Akiyama proposed that the... 

Ferrichromes Hydroxamic acid 3 Species of Aspergillus, Neuro-spora, Paecilomyces, Penicil-lium, Spicaria, Ustilago, Crypto-coccus, Actinomyces, Sireptomy-ces and probably Sphacelotheca... 

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). 

Fig. 19. Plot of redox potentials (Ey2) as a function of pFe3+ values for a series of hexadentate, tetradentate, and bidentate hydroxamic acid siderophores and siderophore mimics. Data from Table V. Legend 1 — ferrioxamine E 2 — ferrioxamine B (4) 3 — H.aLjf4 (11) 4 — H >L 36 (12) 5 - coprogen 6 - ferricrocin 7 - ferrichrome (6) 8 - alcaligin 9 -rhodotorulic acid (3) 10 — NMAHA 11 — AHA 12 — Ly-AHA.

The FhuA receptor of E. coli transports the hydroxamate-type siderophore ferrichrome (see Figure 9), the structural similar antibiotic albomycin and the antibiotic rifamycin CGP 4832. Likewise, FepA is the receptor for the catechol-type siderophore enterobactin. As monomeric proteins, both receptors consist of a hollow, elliptical-shaped, channel-like 22-stranded, antiparallel (3-barrel, which is formed by the large C-terminal domain. A number of strands extend far beyond the lipid bilayer into the extracellular space. The strands are connected sequentially using short turns on the periplasmic side, and long loops on the extracellular side of the barrel. 

As mentioned above, transport of siderophores across the cytoplasmic membrane is less specific than the translocation through the outer membrane. In E. coli three different outer membrane proteins (among them FepA the receptor for enterobactin produced by most E. coli strains) recognise siderophores of the catechol type (enterobactin and structurally related compounds), while only one ABC system is needed for the passage into the cytosol. Likewise, OM receptors FhuA, FhuE, and Iut are needed to transport a number of different ferric hydroxamates, whereas the FhuBCD proteins accept a variety of hydroxamate type ligands such as albomycin, ferrichrome, coprogen, aerobactin, shizokinen, rhodotorulic acid, and ferrioxamine B [165,171], For the vast majority of systems, the substrate specificity has not been elucidated, but it can be assumed that many siderophore ABC permeases might be able to transport several different but structurally related substrates. 

Koster, W. and Braun, V. (1990). Iron(III)hydroxamate transport binding of ferrichrome to the periplasmic FhuD protein, J. Biol. Chem., 265, 21 407-21 410. 

Jalal MAF, Mocharla R, van der Helm D (1984) Separation of Ferrichromes and Other Hydroxamate Siderophores of Fungal Origin by Reversed-phase Chromatography. J Chro-matogr 301 247... 

The EFF calculations yielded a single Cs-symmetric conformation for each type of ferrichrome analog (Figure 4), both with a A-cis configuration of the hydroxamates about the metal when L-amino acids were used. Taken together with the spectroscopic data, pronounced differences were observed for the conformations of these iron complexes. Inspection of the calculated conformations showed that the backbone amide groups may... 

Since the 1,2-HOPO chelators form neutral complexes while the catecholates form charged complexes, it is reasonable to assume that charged species are essential for the enterobactin receptor recognition. The lack of recognition by the ferrichrome analog may well be attributed to the bulky substituents on the hydroxamate moiety in agreement with early observations by Emery and Emery and others ... 

The degeneracy of the non-chiral complexes can be removed by incorporating chiral centers, usually as resolved amino acids, into the arms at close vicinity to the hydroxamate iron binding sites. Thus, only one of the energetically non-equivalent diastereomers predominates, leading to pure enantiomeric iron(III) complexes with defined hehcity that allows assessing stereospecific recognition by the ferrichrome receptor. 

Since modifications at the hydroxamate termini or the projecting side groups on the linking arms were not tolerated by the ferrichrome receptor, most of the modifications were carried out at the epical template site (Figure 6). 

The second group of hydroxamate-based chelators consists of biomimetic ferrichrome analogs modified by introducing hydrophobic amino acids between the template and the hydroxamic acid binding sites 59, 60, 66, 68, 70, 199 and 200. Since they function to withhold iron from cells in contrast to their original function of iron delivery, they were named reversed siderophores (RSF) . ... 

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