Structure ferrioxamines

Fig. 27. Stereochemistry observed for ferrioxamine B resulting in a carbonyl face for the inner coordination shell of Fe(III) that may play a role in recognition. Legend dark grey = O atom light grey = N atom black = Fe atom white = C atom. Figure based on X-ray crystal structure and adapted from Fig. 4b in Ref. (195) and used with kind permission of Springer Science Business Media.

Siderophore-ionophore supramolecular assembly formation via host-guest complexation of the pendant protonated amine arm of ferrioxamine B has been confirmed by X-ray crystallography (Fig. 28) (203). The stability and selectivity of this interaction as a function of ionophore structure, metal ion identity, and counter anion identity were determined by liquid-liquid extraction, isothermal calorimetry, and MS (204 -211). Second-sphere host-guest complexation constants fall in the range 103— 106M-1 in CHC13 and methanol depending on ionophore structure. 

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. 

A multiple-path mechanism has been elaborated for dissociation of the mono- and binuclear tris(hydroxamato)-iron(III) complexes with dihydroxamate ligands in aqueous solution. " Iron removal by edta from mono-, bi-, and trinuclear complexes with model desferrioxamine-related siderophores containing one, two, or three tris-hydroxamate units generally follows first-order kinetics though biphasic kinetics were reported for iron removal from one of the binuclear complexes. The kinetic results were interpreted in terms of discrete intrastrand ferrioxamine-type structures for the di-iron and tri-iron complexes of (288). " Reactivities for dissociation, by dissociative activation mechanisms, of a selection of bidentate and hexadentate hydroxamates have been compared with those of oxinates and salicylates. ... 

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. 

A more complex set of 1,3,5-benzenetricarboxamids, composed of mono- di- and tritopic iron chelating groups, prepared by Tsubouchi and coworkers", showed that tripodal hydroxamates 47 and 48 were able to form tripodal interstrand complexes with one and two iron(III) ions. The tritopic hydroxamate 49 formed preferably ferrioxamine-like intrastrand structures, where each arm binds an iron(III) ion independently. No microbial activity was reported for 47-49. 

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

The crystal structure of five members of the ferrioxamine family has been determined ferrioxamine Di , ferrioxamine E °, desferrioxamine E , the retro-isomer of fer-richrome E and ferrioxamine B . While all of the Fe(III)-ferrioxamine structures (Table 2) crystallize as racemic mixtures of A- and A-cis isomers , the configuration of the binary ferrioxamine-B in EhuD complex (2.0 A resolution) is A-C-trans,cis, indicating that the interaction between ferrioxamine-B and FhuD is enantioselective, and also exhibils geomelric seleclivily. 

While tripodal structures were well adjusted in forming trapping layers, the linear ferrioxamine derivative failed to do so, probably due to their need to fold-up when binding iron thereby disrupting the formed layers. 

Chemical structures of several chelators. Ferroxamine (ferrioxamine) without the chelated iron is deferoxamine. It is represented here to show the functional groups the iron is actually held in a caged system. The structures of the in vivo metal-chelator complexes for dimercaprol, succimer, penicillamine, and unithiol (see text) are not known and may involve the formation of mixed disulfides with amino acids. 

Structures above show the iron complex ferrioxamine B and the related compound, ferrioxamine E, in which the chelate has a cyclic structure. Graph shows success of transfusions and Ironsfusions plus chelation therapy. [Crystal structure kinrty provided by M. Neu, Los Alamos National Laboratory, based on D. Van der Helm and M. Poling. J. Am. Chem. Soc. 1976, 98,82. Graph from R S. Dobbin and R. C. Hider, Iron Chelation Therapy." Chem. Br. 1990,26.565.]... 

Fan angle, 1019 Ferribalamins, 883 Ferrichromes, 970 calcium complexes, 972 Ferridoxins, 773 Ferrioxamines, 970,971 Ferritin, 772 structure, 975 Ferroverdin, 797 structure, 272 Five-membered rings metal complexes, 76 substituents metal complexes, 82 Fluorine... 

C27H4709N Fe. Rf in Solvent System II, 0.72 in Solvent System III, 0.73 (8). Contains l-amino-5-hydroxyaminopentane, succinic acid and acetic acid in the molar ratio 3 2 2. Structure established by synthesis as N-acetyl ferrioxamine B (102). 

Contains l-amino-5-hydroxyaminopentane and succinic acid in the molar ratio 3 3. Structure deduced from characteristic half-step potential, from degradation experiments and from observation that ferrioxamine G may be cyclized to ferrioxamine E. 

Figure 3. Structure of the linear ferrioxamines. The basic structural feature of the ferrioxamines is repeating units of l-amino-5-hydroxyaminopentane and succinic acid. Ferrioxamine E is cyclic with n = 5 and an amide linkage such that there are no R or R substituents, but just a C-N bond.

However, despite large differences in ligand molecular structure, all of the hydroxamate siderophores whose structures have been determined to date have been found to be cis complexes with a coordination geometry about the ferric ion which is substantially identical to the simple tris-(benzhydroxamato)-Fe(III) complex. Thus, while ferrioxamine E is racemic but with a cis geometry (13), x-ray structure analyses of ferrichrome A (14) and ferrichrysin (15) have shown both to be A-cis isomers. 

There is increasing evidence for the beneficial influence of the presence of iron chelators during reperfusion of ischaemic tissue. Clearly Reactions (i), (iii) and (iv) of Scheme 1 do not occur in the absence of loosely bound iron and it is such species which are efficiently scavenged by desferrioxamine (Structure 1, Scheme IB) forming the chemically inert iron complex, ferrioxamine. Thus the... 

Ferrioxamines, typical constituents of culture broths of Actinomycetes, occm as both hnear and cychc compounds containing l-amino-5-hydroxyaminopentane (A-hydroxycadaverine) and succinic acid as building blocks (Figure 1(c)). A cyclic trimer of succinyl-(A-hydroxycadaverine), is named ferrioxamine E. In some cases the pentane moiety is replaced by a butane carbon skeleton (putrescine). The most prominent representative of this siderophore family, desferrioxamine B (Figure 1), has become the drug of choice for the treatment of transfusional iron overload (Section 6.2). The crystal structure of ferric ferrioxamine B has been published recently. Certain derivatives of the ferrioxamines display antibiotic activity and therefore have been designated as ferrimycins. ... 

After Fe + siderophores have docked at the binding pocket of the outer-membrane receptors of E. colt, translocation into the periplasmic space is mediated by the TonB complex. Once released into the periplasm, siderophores are rapidly bound by the specific periplasmic binding proteins FhuD (hydroxamate siderophores), FepB (enterobactin), and FecB (ferric dicitrate).FhuD, for example, exhibits a broad substrate specificity for a variety of hydroxamate siderophores including ferrichrome, coprogen, aerobactin, ferrioxamine B, shizokinen, rhodotorulic acid, and the antibiotic albomycin. The dissociation constants of FhuD with these siderophores range from 0.3 to 5.4 X-ray structures of FhuD... 

Figure 1 Representative siderophores of the hydroxamate and catecholate classes. The hydroxamates are synthesized from the amino acid ornithine that has been modified through hydroxylation and acetylation. Ferrichrome (a) is a prototypical example of the tri-hydroxamate class. Structurally, ferrichrome is a cyclic hexapeptide that consists of three modified ornithine residues (each of which has a hydroxamate side chain) and three glycines. Ferrichrome coordinates ferric iron through its three bidentate hydroxamate side chains. Triacetylfusarinine C (b) is also a cyclic tri-hydroxamate, but the three modified ornithine residues are joined by ester linkages rather than by peptide linkages. Ferrioxamine B (c) is a linear tri-hydroxamate consisting of three peptide-huked modified ornithine residues. Enterobactin (d) is a prototypical example of a catecholate siderophore. It consists of a tri-ester ring from which extend three side chains of chhydroxybenzoyl serine. Each of these siderophores binds ferric iron in a hexadentate manner, which results in full saturation of d orbitals and a very stable complex. Ferric forms are shown in (a) and (b). Desferri-forms are shown in (c) and (d)...

The ferrichromes, fusarinines, and ferrioxamines are typical trihydroxamate siderophores, while enterobactin is a cyclic tricatecholate siderophore. However, there are several exceptions which employ mixed forms of coordination. For example, aero-bactin, schizokinen and arthrobactin contain, in addition to two hydroxamate groups, a a-hydroxy-carboxylate unit which completes the hexadentate ligand structure 30). The recently isolated ferrioxamine H, with two hydroxamate and one carboxylate, is only pentadentate — the sixth coordination site presumably occupied by water 31). 

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). 

The structures of the three iron chelators which are currently approved for clinical use are presented in Figure 22.4. It is now well established that iron chelation therapy reduces the risk of death and improves patient survival during more than four decades of clinical experience with the current reference standard chelator, des-ferrioxamine (DFO). DFO is a hexadentate chelator (as we saw in Chapter 2). However, it is not active by oral... 

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