Hydroxamic acids ferrichromes

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

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 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) . ... 

Growth of Fusariutn sp. at low iron concentration causes the accumulation of a variety of hydroxamic acids of which one has been characterized and named fusarinine, or NS-( s-5-hydroxy-3-methylpent-2-enoyl)-NS-hydroxy-L-ornithine (38). The cis configuration in the unsaturated acyl substituent accounts for the extreme acid lability of the hydroxamic acid bond. Fusarinine is the amino acid unit, bearing the hydroxamic acid linkage, present in ferrirhodin. The characterization of fusarinine has important implications for the biosynthesis of the ferrichrome group for it indicates that the hydroxamic acid bond is inserted at the free amino, acid, rather than at the peptide level. 

Ferrichrome was the first ligand of this type to be isolated (Figure 47). Ferrichrome is a cyclic peptide with three hydroxamic acid side-chains. It gives a neutral complex with Fe . A number of variations having substituents on the hexapeptide or on the acyl group are also found. The ferrichromes are synthesized by fungi, but they are also used by many bacteria as a source of iron, even though they do not synthesize the siderophore themselves. 

Figure 11. Structure of the ferrichromes. The basic structural feature is a cyclic hexapeptide with the three hydroxamic acid linkages provided by a tripeptide of SN-acyl- N-hydroxy- -ornithine. The A-cis coordination iser is shown in each...

A number of substances of the ferrichrome family, containing three hydroxamic acid groups coordinated to a central ferric ion, have been isolated, mainly from microbial sources. These compounds contain a cyclic hexapeptide. Crystal structures for ferrichrome A, cyc/o[LSer-LSer-Gly-Tri ((5-N-methylglutaconyl-5-N-hydroxy-Orn)] (Figs. 11 and 12) (Zalkin et al, 1966), the isomorphous alumichrome A (van der Helm et ai, 1980), and more recently ferrichrysin [LSer-LSer-Gly-tri(5-JV-acetyl- -N-hydroxy-Orn)] (Norrestam et al, 1975) and ferrichrome (Loghry and van der Helm, 1978) have been determined and show that the molecules are essentially isostruc-tural. In these molecules, the ferric ion has approximate octahedral coordination to the six oxygen atoms of the three 5-N-acetyl-5-N-hydroxy or the... 

An iron(III)-binding compound with the properties of a secondary hydroxamic acid has been isolated from supernatant solutions of iron-deficient cultures of a red yeast, Rhodotorula pilimanae (Atkin and Neilands, 1968). The compound rhodotorulic acid (CXVIII) was characterized as LL-3,6-bis (JV-acetyl-3-hydroxyaminopropyl)-2, 5-piperazinedione, i.e., the diketopiperazine of -JV-acetyl-L-5-N-hydroxyomithine. The latter is an amino acid which is a constituent of ferrichromes, albomycins, and fusarinines. In the characterization of rhodotorulic acid, IR, UV, NMR, ORD, and mass spectroscopy were applied. 

Due to their chelating properties hydroxamic acids are of importance in the solubilization and uptake of iron in many microorganisms. Aerobactin participates in the uptake of iron in Escherichia coli. Sideramines, e.g., ferrichrome, are involved in the Fe + uptake in fungi (C 2.2). Some iron-free sideramine-like compounds, e.g., nocardamine, are antibiotics (E 5.2) and inhibit the activity of sideramines by competition. If the Fe +.ion is reduced to Fe + the stability of the hydroxamic acid complexes is reduced and iron may be transferred, for instance from ferrichrome, to compounds with porphyrin ring system (D 10.1). 

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. 

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... 

---