Enterobactin Protonation and Iron Release:  Hexadentate Tris-Salicylate Ligands as Models for Triprotonated Ferric Enterobactin¹

Abstract

Enterobactin mediates iron uptake in Escherichia coli and related bacteria. The structure of the neutral protonated ferric enterobactin complex Fe[H3enterobactin] has been the source of some controversy in the literature. The coordination chemistry of the new model ligands tris[(2-hydroxybenzoyl)-2-aminoethyl]amine (TRENSAM) and tris[(2-hydroxy-3-methoxybenzoyl)-2-aminoethyl]amine (TREN(3M)SAM) demonstrate the previously proposed tris-salicylate mode of binding for ferric enterobactin; they form 1:1 metal−ligand complexes with Fe3+ and Al3+ that bind the metals through tris-salicylato coordination (i.e., the chelate is a six-membered metallocycle with the phenolic and amide oxygens binding the metal center). The ferric and aluminum complexes of TRENSAM are isostructural and crystallize in the monoclinic space group P21/c. The ferric and aluminum complexes of TREN(3M)SAM are nearly isostructural and crystallize in the triclinic space group P1̄, with the same salicylate mode of bonding as the TRENSAM complexes. The TRENSAM ligand and its metal complexes have been investigated by NMR, potentiometric, and spectrophotometric techniques, and the results of these experiments are compared to Fe[H3enterobactin] and a biomimetic analogue Fe[H3MECAM] (which supports growth of E. coli). The properties of Fe[TRENSAM] and Fe[TREN(3M)SAM] represent an iron release pathway for synthetic analogues of enterobactin that are not susceptible to the degradative pathway usual for enterobactin.