The chemical biology and coordination chemistry of putrebactin, avaroferrin, bisucaberin, and alcaligin.

Dihydroxamic acid macrocyclic siderophores comprise four members: putrebactin (putH), avaroferrin (avaH), bisucaberin (bisH), and alcaligin (alcH). This mini-review collates studies of the chemical biology and coordination chemistry of these macrocycles, with an emphasis on putH. These Fe(III)-binding macrocycles are produced by selected bacteria to acquire insoluble Fe(III) from the local environment. The macrocycles are optimally pre-configured for Fe(III) binding, as established from the X-ray crystal structure of dinuclear [Fe(alc)] at neutral pH. The dimeric macrocycles are biosynthetic products of two endo-hydroxamic acid ligands flanked by one amine group and one carboxylic acid group, which are assembled from 1,4-diaminobutane and/or 1,5-diaminopentane as initial substrates. The biosynthesis of alcH includes an additional diamine C-hydroxylation step. Knowledge of putH biosynthesis supported the use of precursor-directed biosynthesis to generate unsaturated putH analogues by culturing Shewanella putrefaciens in medium supplemented with unsaturated diamine substrates. The X-ray crystal structures of putH, avaH and alcH show differences in the relative orientations of the amide and hydroxamic acid functional groups that could prescribe differences in solvation and other biological properties. Functional differences have been borne out in biological studies. Although evolved for Fe(III) acquisition, solution coordination complexes have been characterised between putH and oxido-V(IV/V), Mo(VI), or Cr(V). Retrosynthetic analysis of 1:1 complexes of [Fe(put)], [Fe(ava)], and [Fe(bis)] that dominate at pH < 5 led to a forward metal-templated synthesis approach to generate the Fe(III)-loaded macrocycles, with apo-macrocycles furnished upon incubation with EDTA. This mini-review aims to capture the rich chemistry and chemical biology of these seemingly simple compounds.