Siderophores representative

Investigations on the biosynthesis of siderophores represent a major activity in the field. Considerable effort has been devoted to the chemical synthesis of natmal siderophores, enantiomeric siderophores, and completely synthetic siderophore analogs. This topic will not be covered here and the reader is referred to the corresponding literatme. " ... 

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). 

An examination of equilibrium expressions for different side-rophore denticities will illustrate nature s preference toward hexadentate siderophores. There is a concentration effect when comparing lower denticity siderophores to their higher denticity analogs. pH-independent equilibrium expressions for generic bidentate and hexadentate siderophores are shown below, where Hx represents a hexadentate siderophore and Bd a bidentate siderophore (charges are omitted for clarity). 

Fig. 21. Redox potentials (Ey2) of Fe3+ siderophore and siderophore mimic complexes as a function of pH. Lines represents a fit of Eq. (41) to the data, which are taken from Refs. (3,58,59,91). Adapted with permission from Ref. (4).

Based on experimental data and analysis of sequences available from the databases, we can conclude that different routes for the translocation of iron across the cytoplasmic membrane are possible in bacteria. They can mediate the importation of ferrous iron, and of ferric iron, both in its ionic form and coupled to siderophores or haem. Three of the transport systems represent members of the binding protein-dependent type (a subfamily of ABC transporters or traffic ATPases) (see Section 6.3.2). 

ABC transporters involved in the uptake of siderophores, haem, and vitamin B]2 are widely conserved in bacteria and Archaea (see Figure 10). Very few species lack representatives of the siderophore family transporters. These species are mainly intracellular parasites whose metabolism is closely coupled to the metabolism of their hosts (e.g. mycoplasma), or bacteria with no need for iron (e.g. lactobacilli). In many cases, several systems of this transporter family can be detected in a single species, thus allowing the use of structurally different chelators. Most systems were exclusively identified by sequence data analysis, some were biochemically characterised, and their substrate specificity was determined. However, only very few systems have been studied in detail. At present, the best-characterised ABC transporters of this type are the fhuBCD and the btuCDF systems of E. coli, which might serve as model systems of the siderophore family. Therefore, in the following sections, this report will mainly focus on the components that mediate ferric hydroxamate uptake (fhu) and vitamin B12 uptake (htu). 

Groeger, W. and Koster W. (1998). Transmembrane topology of the two FhuB domains representing the hydrophobic components of bacterial ABC transporters involved in the uptake of siderophores, haem and vitamin B12, Microbiology, 144, 2759-2769. 

A group of related siderophores comprises the desferri- or deferriferrioxamines (occasionally abbreviated as desferrioxamines) or proferrioxamines. Originally they were obtained from Actinomycetes, mainly Nocardia and Streptomyces spp. (187) and later found to be produced also by Erwinia spp. (several representatives) (e.g. (30a, 113,115,180)), Arthrobacter simplex (B), Chromobacterium violaceum (E) (246a), and by Pseudomonas stutzeri (several) (229a, 246,398). They consist of three (or in rare cases four) mono-N-hydroxy-l,4-diaminobutane (putrescine), mono-iV-hydroxy-l,5-diaminopentane (cadaverine) or (rarely) mono-N-hydroxy-1,3-diaminopropane units connected by succinic acid links. The hydroxylated terminus carries an acetyl or a succinyl (as in the structural formula heading Table 6)... 

In this chapter, we wiU concentrate mainly on hydroxamate-based siderophores. However, the most representative example of the catechol-based siderophore family is entero-bactin , a highly Cs-symmetric molecule based on a trilactone ring system derived from three L-serine amino acids. The serine amino groups are extended with three catecholic acid units. Enterobactin binds iron(III) in an octahedral coordination of preferred A-cis configuration (see Figure 1 in Section n.C). 

The hydroxamate-based siderophores discussed in this review represent a large and structurally diversified family (cyclic, tripodal and linear strucmres). This family includes... 

Bacterial siderophores are another class of widespread toxins produced by bacteria. On land, mycobactins and exophilins are the best-known representatives. Those found in the sea, aquachelins, marinobactins, anguibactin, vulnibactin, and aerobactin (Table 12.3.1) are amphiphilic. This is a property that has received great attention for drug delivery problems and in relation to recognition processes (Testa 2000), devising efBcient algorithms for computer calculation (Fisher 2000). 

Ligand 3.147 is part of the class of siderands (synthetic siderophores), and displays further useful properties such as stability towards oxidation of the catechol binding sites and hydrolysis resistance. This represents one of the few examples where man-made molecules are more effective than their natural precursors. 

FIGURE I Schematic representation of the cycling Fe and P in humic-rich systems DOM complexes both essential elements and renders them unavailable to organisms without transformation. Y represents siderophore ligand, and Fe is iron in free ionic form. 

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. ... 

Figure 1 Structures of representative hydroxamate siderophores (a) ferrichromes (R = Me, X = = H, ferrichrome R = Me,...

Figure 2 Structures of representative catecholate and mixed-ligand siderophores (a) enterobactin (b) parabactin (c) mycobacins (R = various alkyl chains, = R = R = MeorH.R = alkyl chains or H ) (d) fluorescent chromophore of pseudobactins and pyoverdins...

The spin Hamiltonian nsnally employed for the analysis of siderophores can be represented by eqnation (1) ... 

Figure 10 A schematic drawing of the cell envelope of E. coli consisting of the cytoplasmic membrane, the periplasm, and the outer membrane. Various proteins are shown, sets of which represent specific siderophore-transport systems. Outer-membrane receptors (OMR) shown here are FepA (enterobactin), lutA (aerobactin), Fee A (Fe dicitrate), FhuA (ferrichrome), and FhuE (coprogen, Fe rhodotorulate, and ferrioxamine B). FoxA (ferrioxamine B), is not a receptor of E.coli, but of the closely related Salmonella. Not shown here are the receptors Fiu and Cir (Fe (DHBS) n indicates 3 possible linear degradation products of enterobactin) and FeO, a transport system for Fe . Details are discussed in Section 5.1...

In the past few years, crystal structmes have been published of three of the seven outer-membrane-siderophore receptors from E.coli, namely of FepA,FhuA, and FecA. FepA and FhuA represent similar monomeric transmembrane proteins that are composed of 22 antiparallel B-strands of approximately 70 A height (Figme 11). The right-handed twist of the /3-strands produces an ellipticalshaped barrel with a diameter of 35 x 47 A constituting a transmembrane pore. Targe extracellular loops extend... 

The predominant class of intracellular iron-storage compounds is represented by ferritin in eukaryotes and bacterioferritin in prokaryotes (see Iron Proteins for Storage Transport their Synthetic Analogs). In various in vivo Mdssbauer spectroscopic studies on siderophore uptake in fungi, it was realized that siderophores can also function as intracellular iron-storage compounds. In the ascomycete Neurospora crassa, the transport siderophore coprogen represents an intracellular transient iron pool. A major part of coprogen-bound iron is transferred to a... 

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)...

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