Siderophores

FIGURE 4.18 Chemical structures of selected siderophores to illustrate the four major structural classes (a) Enterobactin (b) Yersiniabactin (c) Staphyloferrin (d) ferrichrome. 

The importance of iron for a bacteria like E. coli can be illustrated by the fact that 14 genes alone are required for enterobactin-mediated iron uptake, including those for its synthesis, export, transport of the ferric-enterobactin back into the cell and iron release. In total, E. coli has at least eight uptake systems for iron, encoded by some 50 genes. 

This family of charmers includes Y. pestis, the causative agent of the plague. 

Because they often function as virulence factors, the enzymes involved in siderophore biosynthesis are potential targets for developing antimicrobial strategies. The mechanisms of siderophore biosynthesis follow the same fundamental biosynthetic logic involving similar protein machinery, which we describe in greater detail in Chapter 5 for fatty acid biosynthesis. It is also used in the microbial biosynthesis of many important natural products polyketides and peptides (including many antibiotics). Essentially, as is illustrated in Fig. 4.20, for enterobactin, it involves 

Al-Karadaghi, S., Franco, R., Hansson, M., Shelnutt, J. A., Isaya, G., Ferreira, G. C. (2006). Chelatases distort to select Trends in Biochemical Sciences, 31, 135—142. 

Institut fur Organische Chemie, Universitat zu Koln, Greinstr. 4, 50939 Kdln, Germany e-mail aco88 uni-koeln.de 

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. 

Obviously siderophores can be potent virulence factors of pathogenic bacteria. Siderophores in many cases have elaborate structures providing recognition only by the receptor site of the producing species. This renders a pirating by competing microorganisms more difficult. The structural specificities of siderophores have been used for classification purposes of bacterial species (see especially pyoverdins, Sect. 2.1). 

Ga complexes are frequently analyzed for two reasons. Ga also forms octahedral structures and it has almost the same ion radius as Fe (62 vs. 65 pm). In contrast to Fe it is diamagnetic and its complexes are therefore amenable to NMR analysis. Also in contrast to Fe it cannot be reduced and therefore it is used for uptake studies interested in the fate of the complex in the cell. 

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 

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The structures of 5-ethyl-1 ]-methyl-9-oxo-5,l l-dihydro-9/7-pyrido[2,1-6]-quinazohne-8-carboxylic acid (00K669), the chromophore 4 of isopyoverdin siderophores (01T1019), and that of 5,5n,6,7,8,9-hexahydro-l l//-pyrido [2,]-6]quinazoline (99SL1383) were justified by X-ray analysis. 

Raymond, K. N., Muller, G., and Matzanke, B. F. Complexation of Iron by Siderophores A Review of Their Solution and Structural Chemistry and Biological Function. 123 49-102 (1984). 

Complexation of iron by siderophores. A review of their solution and structural chemistry and biological function. K. N. Raymond, G. Muller and B. F. Matzanke, Top. Curr. Chem., 1984,123, 49 (227). 

Siderophore mediated absorption of iron. R. C. Hider, Struct. Bonding (Berlin), 1984, 58, 25 (324). 

Chattaraj PK, Parr RG (1993) Density Functional Theory of Chemical Hardness. 80 11-26 Cheh AM, Neilands JP (1976) The j -Aminoevulinate Dehydratases Molecular and Environmental Properties. 29 123-169 Chimiak A, Neilands JB (1984) Lysine Analogues of Siderophores. 58 89-96 Christensen JJ, see Izatt RM (1973) 16 161-189... 

Henry M, Jolivet JP, Livage J (1991) Aqueous Chemistry of Metal Cations Hydrolysis, Condensation and Complexation. 77 153-206 Hider RC (1984) Siderophores Mediated Absorption of Iron. 57 25-88 Hill HAO, Rdder A, Williams RJP (1970) The Chemical Nature and Reactivity of Cytochrome P-450. 8 123-151... 

Neilands JB (1972) Evolution of Biological Iron Binding Centers. II 145-170 Neilands JB (1984) Methodology of Siderophores. 58 1-24... 

Siderophores like desferrioxamine may, therefore, find increasing applications not only in the treatment of iron poisoning and iron-overloaded disease states but also as chemotherapeutic agents, although the possible problems noted above cannot be ignored. 

Jones R.L. Grady R.W. (1983) Siderophores as antimicrobial agents. EurJ Clin Microbiol, 2, 411-413. 

In response to iron deprivation, E. chrysanthemi induces the synthesis of siderophores and also the transcription of pectate lyase genes (52). The pelB, pelC, pelE and pelL genes are induced under Umited iron-deprivation whereas pelD is only induced under severe iron-deprivation (53). Iron sensing in E. 

Soft rot spreading depends on the efficiency of the iron uptake pathway mediated by the siderophore chrysobactin. Biosynthesis of the ferrichrysobactin outer membrane receptor (Fct) and of the chrysobactin precursor, i.e. the activated form of 2,3-dihydroxybenzoic acid, are encoded by an operon,/cr ebsCEBA [3]. 

Iff the light of the above data, we examined the incidence of the cbrA21 (chrysobactin siderophore produced constitutively) and kdgR mutations on the transcriptional activity of pel genes. We chose to study pelD uidA and pelE uidA that proved to be well expressed in planta and whose suceptibility to iron limitation is different ... 

The mutant L37 cbrA21 is affected as regards to its iron uptake pathway mediated by the siderophore achromobactin. Because this mutation results in derepression of the chrysobactin mediated iron transport pathway, the mutant is probably less susceptible to iron deprivation than wild-type cells are, when entering the host. This results in a delay in Pels production thus leading to delayed symptoms, as reported by Sauvage and Expert (1994). 

Mahd, B., Masclaux, C., Rauscher, L., Enard, C., and Expert, D. 1995. Differential expression of two siderophore-dependent-iron acquisition pathways in Erwinia cf santhemi 3937 characterization of a novel ferrisiderophore permease of the ABC transporter family. Mol. Microbiol. 18 33-43... 

Wandersman C, P Delepelaire (2004) Bacterial iron sources from siderophores to hemophores. Annu Rev Microbiol 58 611-647. 

Although Fe is required as a trace element, its uptake is critically regulated since excess leads to the generation of toxic hydroxyl radicals, and complex interactions involving Fe(II) and Fe(HI) exist within the cell (Touati et al. 1995). The role of Fe(III)-complexing siderophores in maintaining homeostasis has been noted in Chapter 3, Part 5. Details of the role of Fe and its relation to the... 

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