Enterobactins

Enterobacter aerogenes Enterobacter cloacae Enterobacteriaceae Enterobacter ridant Enterobactin Enterococcus faecalis Enterohepatitis Enteroviruses... 

Enterobactin (ent), the cycHc triester of 2,3-dihydroxy-A/-benzoyl-l-serine, uses three catecholate dianions to coordinate iron. The iron(III)-enterobactin complex [62280-34-6] has extraordinary thermodynamic stabiUty. For Fe " +ent , the estimated formal stabiUty constant is 10 and the reduction potential is approximately —750 mV at pH 7 (23). Several catecholate-containing synthetic analogues of enterobactin have been investigated and found to have lesser, but still impressively large, formation constants. 

The first synthesis of enterobactin, a microbial chelator and transporter of environmental iron, was accomplished by the coupling of three protected L-serine units and macrocyclization by the double activation method. 

The prototype of the catechol siderochromes is enterobactin (70) [enterochelin in the terminology of Australian workers (77)]. Enterobactin occurs commonly throughout the enteric bacteria and enterobactin (enterochelin) is the natural carrier invoked when the organisms are... 

The catechol-type ligand appears to be restricted to siderochromes derived from prokaryotic microorganisms. Klebsiella oxytoca, an organism closely related to members of the genus Aerobacter, forms the 2,3-dihy-droxy-N-benzoyl derivates of serine and threonine in three day cultures (72). It is not known if the latter amino acid occurs in trimers but examination of space-filling CPK models does indicate that enterobactin could accomodate a methyl substituent on the carbon of the serine residue. Catechols occur in higher protist organisms but their formation... 

Figure 3.3 Comparison of the FepA and FhuA crystal structures. A portion of the 13-barrel (in violet is removed to show the globular cork domain (in yellow) that inserts from the periplasm into the channel of the 11-barrel. FhuA is loaded with ferrichrome (iron is shown as a green ball) (Ferguson et ah, 1998 Locher et ah, 1998). The FepA crystal structure does not reveal Fe3+-enterobactin, but the FepA structure shown might be partially occupied by enterobactin (Buchanan et ah, 1999). 

The crystal structure of FepA, the outer membrane transporter of Fe3+-enterobactin, has also been determined (Figure 3.3), and has a structure similar to the FhuA structure (Buchanan et al, 1999). In the FepA structure, the TonB box (residues 12-18) can be clearly seen located inside the barrel and extending into the periplasm, as one would expect from its interaction with the periplasmic portion of TonB. 

The ent-fes-fep gene cluster is necessary for the synthesis of enterobactin and transport of the iron loaded siderophore. The fes gene product was shown to be necessary for utilization of the siderophore-bound iron inside the cell. The protein has an esterase activity which cleaves the ester bonds of the cyclic 2,3-dihydroxybenzoylserine ester in enterobactin. However, the esterase activity of Fes does not seem to be important for iron mobilization since Fes is also necessary for the utilization of iron from enterobactin analogues which do not have ester bonds (Heidinger et ah, 1983). No reductase activity has been found in Fes (Brickman and McIntosh, 1992) or in any other protein encoded in the ent-fes-fep gene cluster. 

The majority of Fur-regulated gene products are involved in iron uptake. Genes for transport and biosynthesis of enterobactin have been studied in E. coli K-12 (Earhart, 1996). It is assumed that this system is found in nearly every E. coli strain. Also the ferrichrome transport system seems to have a very broad distribution. The ferric citrate transport system (fee), however, is only present in some E. coli strains and may be part of a pathogenicity island. The aerobactin and yersiniabactin biosynthesis and transport systems are not found in all E. coli strains and are integrated into pathogenicity islands (Schubert et al., 1999). The ability to utilize haem seems also to be a specific pathogenicity-related adaptation. Haem transport systems are used in the animal or human host, where transferrin and lactoferrin create an iron-poor environment for bacteria. 

Rings with rigid pendant arms . The interesting ligand tris(2,3-dihy-droxybenzoyl)l,5,9-triazacyclotridecane (102), was synthesized specifically to act as a reagent for Fe(in) (Weitl Raymond, 1979). It is structurally quite closely related to enterobactin (103), the natural molecule used by E. coli to transport Fe(m) through its cell walls. The protonation and complexation equilibria of Fe(m) with (102) have been... 

The effect of the amino acid spacer on iron(III) affinity was investigated using a series of enterobactin-mimic TRENCAM-based siderophores (82). While TRENCAM (17) has structural similarities to enterobactin, in that it is a tripodal tris-catechol iron-binding molecule, the addition of amino acid spacers to the TRENCAM frame (Fig. 10) increases the stability of the iron(III) complexes of the analogs in the order ofbAla (19)complex stability is attributed to the intramolecular interactions of the additional amino acid side chains that stabilize the iron-siderophore complex slightly. 

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