Siderophores structural types

A microbial strain may produce more than one siderophore. There are variations in fatty acid chains of a lipophilic part or in the amino acids making up the backbone, as well as released intermediates of the biosynthetic chain. These variations belong all to the same structural pattern. However, there is also the possibility that so-called secondary siderophores are encountered. They constitute a different structural type, usually less complex in their constitution but also less efficient in binding Fe " than the primary ones. Secondary siderophores will be produced when the demand for iron is not so severe or in case there is a genetic defect impeding the production of the primary ones. Examples will be found throughout the review. 

Siderophores can be classified by different criteria. In this review related structural types will be grouped together. Some arbitrariness cannot be avoided due to the occurrence of mixed types . Cross-references will then be given. Trivial names... 

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. 

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). 

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. 

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. 

Boopathi E, Rao KS (1999) A Siderophore from Pseudomonas putida Type Al Structural and Biological Characterization. Biochim Biophys Acta 1435 30... 

Chakraborty RN, Patel HN, Desai SB (1990) Isolation and Partial Characterization of Catechol-Type Siderophore from Pseudomonas stutzeri. Curr Microbiol 20 283 Challis GL (2005) A Widely Distributed Bacterial Pathway for Siderophore Biosynthesis Independent of Nonribosomal Peptide Synthetases. ChemBioChem 6 601 Chambers CE, McIntyre DD, Mouck M, Sokol PA (1996) Physical and Structural Characterization of Yersiniophore, a Siderophore Produced by Clinical Isolates of Yersinia entero-colitica. BioMetals 9 157... 

Hossein MB, Jalal MAE, Benson BA, Barnes CL, van der Helm D (1987) Structure and Conformation of Two Coprogen-type Siderophores Neocoprogen I and Neocoprogen II. J Am Chem Soc 109 4948... 

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 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. 

Relatively few membrane transport proteins have been structurally characterized. Some of the best understood examples to date are the lactose permease and glycerol-3-phosphate transporter and the Ca + P-type ATPase (which is a primary ion pump). Other structurally well-characterized transport proteins include the bacterial porins and siderophore receptor proteins. In addition structures have been determined for several ion channels and additional bacterial transporters that are either directly relevant to or models for proteins important in drug transport. The following web sites maintained by Hartmut Michel and Stephen White respectively, contain exceptionally useful listings of these and other solved membrane protein structures and are frequently updated ... 

NRPS-independent siderophore (NTS) synthetases constitute another class of biosynthetic enzymes that can be divided into three types according to their amino acid sequence.These types are proposed to be specific for different substrates. Thus, type A enzymes are specific for citric acid, type B enzymes are proposed to be specific for a-ketoglutaric acid, and type C enzymes are specific for derivatives of citric or succinic acid. The type C enzymes are further divided into modular and iterative subtypes depending on whether they catalyze one or multiple condensation reactions. Thus for novel NTS synthetase systems uncovered by genome sequencing, structural features of their metabolic products can often be predicted. 

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