Ins and Outs: Recent Advancements in Membrane Protein-Mediated Prokaryotic Ferrous Iron Transport

Abstract

Iron is an essential nutrient for virtually every living organism, especially pathogenic prokaryotes. Despite its importance, however, both the acquisition and the export of this element require dedicated pathways that are dependent on oxidation state. Due to its solubility and kinetic lability, reduced ferrous iron (Fe2+) is useful to bacteria for import, chaperoning, and efflux. Once imported, ferrous iron may be loaded into apo and nascent enzymes and even sequestered into storage proteins under certain conditions. However, excess labile ferrous iron can impart toxicity as it may spuriously catalyze Fenton chemistry, thereby generating reactive oxygen species and leading to cellular damage. In response, it is becoming increasingly evident that bacteria have evolved Fe2+ efflux pumps to deal with conditions of ferrous iron excess and to prevent intracellular oxidative stress. In this work, we highlight recent structural and mechanistic advancements in our understanding of prokaryotic ferrous iron import and export systems, with a focus on the connection of these essential transport systems to pathogenesis. Given the connection of these pathways to the virulence of many increasingly antibiotic resistant bacterial strains, a greater understanding of the mechanistic details of ferrous iron cycling in pathogens could illuminate new pathways for future therapeutic developments.

Functional characterization of the Co2+transporter AitP inSinorhizobium meliloti: a new player in Fe2+homeostasis

“…Thus, we heterologously overexpressed AitP in Δ fieF E. coli strain (not shown). FieF was previously described as an Fe 2+ transporter [31, 32] and thus the genotypic background lacking FieF would allow measurement of Fe 2+ with low background signal. After protein induction everted membrane vesicles were obtained and energized by pre-incubation with the electron donor NADH (or lactate) generating a H + -electrochemical gradient (not shown).…”

“…FieF was previously described as an Fe 2+ transporter [31,32] and thus the genotypic background lacking FieF would allow measurement of Fe 2+ with low background signal.…”

The structure of Vibrio cholerae FeoC reveals conservation of the helix-turn-helix motif but not the cluster-binding domain

“…For many pathogenic bacteria, iron is typically obtained from a host as siderophore-bound ferric iron (Fe 3+ ), iron protoporphyrin IX (heme), and/or ferrous iron (Fe 2+ ), and the acquisition of this element is necessary to establish and to maintain infection [2][3][4][5][6][7]. Methods of Fe 3+ and heme acquisition have been well-characterized, but pathways for Fe 2+ uptake are less well-understood.…”

“…The ferrous iron transport system (Feo) is the most conserved and broadly-distributed system dedicated to Fe 2+ transport in prokaryotes [5]; however, the precise mechanism of Feomediated iron transport remains unclear. The feo operon is generally bipartite and encodes for FeoA, a small (ca.…”

The structure of Vibrio cholerae FeoC reveals conservation of the helix-turn-helix motif but not the cluster-binding domain

“…The ferrous iron transport system (Feo) is the most conserved and broadly-distributed system dedicated to Fe 2+ transport in prokaryotes [5]; however, the precise mechanism of Feo-mediated iron transport remains unclear. The feo operon is generally bipartite and encodes for FeoA, a small ( ca .…”