Emergence of Ferrichelatase Activity in a Siderophore-Binding Protein Supports an Iron Shuttle in Bacteria

Siderophores are small-molecule high-affinity multi­dentate chelators selective for ferric iron that are produced by pathogenic microbes to aid in nutrient sequestration and enhance virulence. In Gram-positive bacteria, the currently accepted paradigm in sidero­phore-mediated iron acquisition is that effluxed metal-free sidero­phores extract ferric iron from biological sources and the resulting ferric sidero­phore complex undergoes diffusion-controlled association with a surface-displayed sidero­phore-binding protein (SBP) followed by ABC permease-mediated trans­location across the cell envelope powered by ATP hydrolysis. Here we show that a more efficient paradigm is possible in Gram-positive bacteria where extra­cellular metal-free sidero­phores associate directly with apo-SBPs on the cell surface and serve as non-covalent cofactors that enable the holo-SBPs to non-reductively extract ferric iron directly from host metallo­proteins with so-called “ferri­chelatase” activity. The resulting SBP-bound ferric sidero­phore complex is ready for import through an associated membrane permease and enzymatic turnover is achieved through cofactor replacement from the readily available pool of extra­cellular sidero­phores. This new “iron shuttle” model closes a major knowledge gap in microbial iron acquisition and defines new roles of the sidero­phore and SBP as cofactor and enzyme, respectively, in addition to the classically accepted roles as a transport substrate and receptor pair. We propose the formal name “sidero­phore-dependent ferri­chelatases” for this new class of catalytic SBPs.