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

Nathaniel P. Endicott, Gerry Sann M. Rivera, Jinping Yang, Timothy A. Wencewicz

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)493-506
Number of pages14
JournalACS Central Science
Volume6
Issue number4
DOIs
StatePublished - Apr 22 2020

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