Hydroxamates, siderophores

The po.ssible role of a chelate reductase for iron uptake from microbial siderophores has been examined for several plant species (30,47). With certain microbial siderophores such as rhizoferrin and rhodotorulic acid, the reductase may easily cleave iron from the siderophore to allow subsequent uptake by the ferrous iron transporter. However, with the hydroxamate siderophore, ferrioxamine B, which is produced by actinomycetes and u.sed by diverse bacteria and fungi, it has been shown that the iron stress-regulated reductase is not capable... 

There is some evidence that the iron-sulfur protein, FhuF, participates in the mobilization of iron from hydroxamate siderophores in E. coli (Muller et ah, 1998 Hantke, K. unpublished observations). However, a reductase activity of FhuF has not been demonstrated. Many siderophore-iron reductases have been shown to be active in vitro and some have been purified. The characterization of these reductases has revealed them to be flavin reductases which obtain the electrons for flavin reduction from NAD(P)H, and whose main functions are in areas other than reduction of ferric iron (e.g. flavin reductase Fre, sulfite reductase). To date, no specialized siderophore-iron reductases have been identified. It has been suggested that the reduced flavins from flavin oxidoreductases are the electron donors for ferric iron reduction (Fontecave et ah, 1994). Recently it has been shown, after a fruitless search for a reducing enzyme, that reduction of Co3+ in cobalamin is achieved by reduced flavin. Also in this case it was suggested that cobalamins and corrinoids are reduced in vivo by flavins which may be generated by the flavin... 

Another factor that will affect the complex redox potential is the architecture of the siderophore. A plot of ferri-siderophore redox potentials as a function of pFe for a series of hydroxamate complexes of differing denticity (shown in Fig. 19) exhibits a trend. The trend demonstrates that hydroxamate siderophores of higher denticity will form complexes with more negative E1/2 values than analogous siderophores of lower denticity. 

Matsumoto et al. demonstrated that the removal of iron from diferric transferrin by the tris-hydroxamate siderophore mimic TAGE occurs in two discreet steps (90). The slower step corresponds to iron removal from the more stable C-lobe site on transferrin and the faster step to removal from the N-lobe. The rates of removal are similar to the rates of removal of iron from diferric transferrin by desferrioxamine B (4), signifying similar mechanisms of removal between the two systems (90). 

A hydroxamate siderophore from Salmonella typhimurium is described as containing isoleucine/leucine, phenylalanine and valine, but not serine and lysine. Further details are not given (290a). For other Salmonella siderophores see Sect. 2.7. 

Fig. 5. Acyl residues encountered in fungal hydroxamate siderophores...

The smallest hydroxamate siderophore is A(-methyl-(V-thioformylhydroxyla-mine, CH3-N(OH)-CHS, named thioformin 100) or fluopsin (325). The synthesis was described (CH3-N(OH)-CHO + P2S5 or CH3-N(OH)-H + HCSSK) (100,166a). It forms a purple Fe Ligs complex. Pseudomonas mildenbergii produces W-methyl-Af-phenylacetylhydroxylamine (CH3-N(OH)-CO-CH2-C6Hs) (159), which also forms a purple Fe " complex. 

Haselwandter K, Dobemigg B, Beck W, Jung G, Cansier A, Winkelmann G (1992) Isolation and Identification of Hydroxamate Siderophores of Ericoid Mycorrhizal Fungi. BioMetals 5 51... 

Ishimaru CA, Loper JE (1992) High-Affinity Iron Uptake Systems Present in Erwinia carotovora subsp. carotovora Include the Hydroxamate Siderophore Aerobactin. J Bacteriol 174 2993... 

Jalal MAF, Mocharla R, van der Helm D (1984) Separation of Ferrichromes and Other Hydroxamate Siderophores of Fungal Origin by Reversed-phase Chromatography. J Chro-matogr 301 247... 

The first of the coprogens (fungal sideramines ) was reported in 1973. Neocoprogen I (280) and neocoprogen II (281) are linear tris-hydroxamate siderophores whose chelating groups are derived from A -hydroxy-A -acylated ornithines. Neocoprogen I is the first structurally established example of a irons tris-hydroxamate siderophore. Subsequent studies have dealt with... 

Bartholdy BA etal, Hydroxamate siderophore synthesis hy Phialocephalafortinii, a typical dark septate fungal root endophyte, BioMetals 14 33-42, 2001. 

Haselwandter K etal, Isolation and identification of hydroxamate siderophores of ericoid mycorrhizal fungi, BioMetals 5 51-56, 1992. 

A. The Major Hydroxamate Siderophore Families and Their Analogs. . . 759... 

Once the siderophore-iron complexes are inside the bacteria, the iron is released and utilized for vital cell functions. The iron-free hydroxamate siderophores are commonly re-excreted to bring in an additional iron load (Enterobactin is at least partially degraded by a cytoplasmic esterase This cycle is repeated until specific intracellular ferric uptake regulation proteins (Fur proteins) bind iron, and signal that the intracellular iron level is satisfactory, at -which point ne-w siderophore and siderophore-receptor biosynthesis are halted and the iron-uptake process stops. This intricate feedback mechanism allows a meticulous control over iron(III) uptake and accumulation against an unfavorable concentration gradient so as to maintain the intracellular iron(III) level within the required narrow window. Several excellent reviews concerning siderophore-iron transport mechanisms have been recently published i.3,i6, is,40,45,60-62 ... 

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. 

Kraemer, S.M. Hering, J.G. (1997) Influence of solution saturation state on the kinetics of ligand-controlled dissolution of oxide phases. Geochim. Cosmochim. Acta 61 2855-2866 Kraemer, S.M., Xu, J., Raymond, K.N. Spo-sito, G. (2002) Adsorption of Pb(II) and Eu(III) by oxide minerals in the presence of natural and synthetic hydroxamate sidero-phores. Environ. Sd. Technol. 36 1287-1291 Kraemer, S.M. Cheah, S.-F. Zapf, R. Xu, J. Raymond, KN. Sposito, G. (1999) Effect of hydroxamate siderophores on Fe release and Pb(II) adsorption by goefhite. Geochim. Cosmochim. Acta 63 3003—3008 Kratohvil, S. Matijevic, E. (1987) Preparation and properties of coated uniform colloidal partides. I. Aluminum (hydrous) oxide on hematite, diromia, and titania. Adv Ceram. Mater. 2 798-803... 

M. Holzberg and W.M. Artis, Hydroxamate siderophore production by opportunistic and systemic fungal pathogens, Infect. Immun., 40, 1134, 1983. 

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