2.3- Dihydroxybenzoyl serine

In microorganisms p-hydroxybenzoic ( ), salicylic ( ) and 2,3-dihydroxybenzoic ( 5) acids are all synthesised via chorismic acid > ° in metabolism which is purposeful in character (Fig. 3). -Hydroxybenzoic acid (2 is thus an intermediate in the biosynthesis of the ubiquinones >and 2,3-dihydroxybenzoyl serine (26), as its cyclic trimer enterochelin, is intimately involved in iron transport in some bacteria. Protocatechuic acid ( ) in contrast is probably formed as a shunt-metabolite in certain mutants of Aerobacter aerogenes which are blocked in the biosynthesis of the aromatic amino acids. 

Cultures of Escherichia coli and Aerobacter aerogenes grown under low iron conditions have been shown to contain, during the early exponential phase of growth, 2,3-dihydroxybenzoic acid (43), N-2,3-dihydroxybenzoyl serine (48) and a cyclic trimer enterochelin (45). Subsequently a linear dimer (47) and linear trimer (46) of N-2,3-dihydroxybenzoyl serine are formed apparently from the... 

A-(dihydroxybenzoyl)serine linear trimer (257) and its dimer analogue are 10" and 10 , respectively. Enthalpies of formation for the Fe complexes of the trimer and of enterobactin are reported. Linear hexapeptides and decapeptides bearing catechol units derived from dopa (dihydrox ghenylalanine) form stable complexes with Fe +, with stability constants in the range... 

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. Triacetylfusarmine C (b) is also a cyclic tri-hydroxamate, but the three modified ornithine residues are Joined by ester Unkages rather than by peptide linkages. Ferrioxamine B (c) is a linear tri-hydroxamate consisting of three peptide-Unked 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 dihydroxybenzoyl 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)...

In addition to the hydroxamates there are other low molecular weight species produced by protista which chelate iron. In general, these chelators contain the 2,3-dihydroxybenzoyl moiety, such as 2,3-dihydroxy-N-benzoyl-Z,-serine, 2,3-dihydroxy-N-benzoylthreonine, 2,3-dihydroxy-N-benzoyl-glycine, and enterochelin (84). 

The best known example is enterobactin (otherwise called enterochelin), which is produced apparently by all enteric bacteria. It has three 2,3-dihydroxybenzoyl groups attached to a macrocyc-lic lactone derived from three residues of L-serine condensed head-to-tail. The structures of enterobactin and its iron complex are shown in Figure 45, which shows that the iron is bound by six phenolate oxygen atoms in an octahedral environment. Enterobactin has the highest known affinity for Fem, with log K = 52 at pH 7.4.1182 The iron(III) complex can exist as isomeric forms, which may be associated with selectivity in binding to the receptor site. 

The siderophore enterobactin (enterochelin) (64) is a cyclic lactone of three N-(2,3-dihydroxybenzoyl) L-serine moieties produced by E. coli under iron stress. Enterobactin (64) was first isolated from iron-limited cultures of Salmonella typhimur-ium [83], E. coli [84], and Aerobacter aerogenes [84]. Structural analysis has confirmed that 64 chelates iron as a hexadentate ligand via the two hydroxyl groups on each catechol moiety (see Fig. 13) [85]. Of all the siderophores characterized to date, 64 has been shown to have the highest affinity for ferric iron, with a stability constant of 1052 M 1 [86, 87], which is remarkable, considering the affinity of EDTA for iron is 27 orders of magnitude lower. In mammals, serum albumin [88] and siderocalin [89, 90] bind the hydrophobic 64 which impedes siderophore-mediated transfer of iron to bacteria. Consequently, bacteria such as E. coli and... 

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