Control of Iron Metabolism in Bacteria

Andrews, Simon C.; Norton, Ian D.; Salunkhe, Arvindkumar; Goodluck, Helen; Aly, Wafaa S. M.; Mourad-Agha, Hanna; Cornélis, Pierre

doi:10.1007/978-94-007-5561-1_7

Cited by 48 publications

(51 citation statements)

References 212 publications

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“…In addition, because Fur directly represses transcription of RyhB (32), Fur indirectly affects the stability of the iscSUA-hscBA-fdx transcript, thus promoting Fe-S cluster biogenesis via the Suf pathway when Fe is limiting. Finally, since Fur regulates expression of Fe uptake pathways (47), the amount of Fe available for building Fe-S clusters is ultimately dictated by Fur. This in turn provides a way to reestablish use of the housekeeping Isc pathway following adaptation to stress.…”

Section: Discussionmentioning

confidence: 99%

Coordinate Regulation of the Suf and Isc Fe-S Cluster Biogenesis Pathways by IscR Is Essential for Viability of Escherichia coli

Mettert

Kiley

2014

J Bacteriol

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Fe-S cluster biogenesis is essential for the viability of most organisms. In Escherichia coli, this process requires either the housekeeping Isc or the stress-induced Suf pathway. The global regulator IscR coordinates cluster synthesis by repressing transcription of the isc operon by [2Fe-2S]-IscR and activating expression of the suf operon. We show that either [2Fe-2S]-IscR or apoIscR can activate suf, making expression sensitive to mainly IscR levels and not the cluster state, unlike isc expression. We also demonstrate that in the absence of isc, IscR-dependent suf activation is essential since strains lacking both the Isc pathway and IscR were not viable unless Suf was expressed ectopically. Similarly, removal of the IscR binding site in the sufA promoter also led to a requirement for isc. Furthermore, suf expression was increased in a ⌬isc mutant, presumably due to increased IscR levels in this mutant. This was surprising because the iron-dependent repressor Fur, whose higher-affinity binding at the sufA promoter should occlude IscR binding, showed only partial repression. In addition, Fur derepression was not sufficient for viability in the absence of IscR and the Isc pathway, highlighting the importance of direct IscR activation. Finally, a mutant lacking Fur and the Isc pathway increased suf expression to the highest observed levels and nearly restored [2Fe-2S]-IscR activity, providing a mechanism for regulating IscR activity under stress conditions. Together, these findings have enhanced our understanding of the homeostatic mechanism by which cells use one regulator, IscR, to differentially control Fe-S cluster biogenesis pathways to ensure viability.

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Section: Discussionmentioning

confidence: 99%

Coordinate Regulation of the Suf and Isc Fe-S Cluster Biogenesis Pathways by IscR Is Essential for Viability of Escherichia coli

Mettert

Kiley

2014

J Bacteriol

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“…These include the production of siderophores (iron chelators capable of binding Fe 3+ with association constants that can exceed 10 30 ), heme acquisition systems aimed at utilizing host-heme as an iron source, transferrin and lactoferrin receptors, and Fe 2+ importers. 4–7 Efficient deployment of these iron uptake strategies depends on intact iron homeostasis machinery, which endows the bacterial cell with the ability to sense intracellular and environmental iron levels, and to coordinate responses to procure iron, or to defend from potential iron-induced toxicity. To maintain iron homeostasis bacteria must balance the synthesis and secretion of iron scavenging systems, the capture and import of iron-scavenger complexes, the incorporation of the nutrient into iron-utilizing proteins, and the storage of iron in iron storage proteins, which can also provide a source of iron when external supplies are limited.…”

Section: Introductionmentioning

confidence: 99%

Inhibiting the BfrB:Bfd interaction in Pseudomonas aeruginosa causes irreversible iron accumulation in bacterioferritin and iron deficiency in the bacterial cytosol

et al. 2017

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Iron is an essential nutrient for bacteria but the reactivity of Fe2+ and the insolubility of Fe3+ present significant challenges to bacterial cells. Iron storage proteins contribute to ameliorating these challenges by oxidizing Fe2+ using O2 and H2O2 as electron acceptors, and by compartmentalizing Fe3+. Two types of iron-storage proteins coexist in bacteria, the ferritins (Ftn) and the heme-containing bacterioferritins (Bfr), but the reasons for their coexistence are largely unknown. P. aeruginosa cells harbor two iron storage proteins (FtnA and BfrB), but nothing is known about their relative contributions to iron homeostasis. Prior studies in vitro have shown that iron mobilization from BfrB requires specific interactions with a ferredoxin (Bfd), but the relevance of the BfrB:Bfd interaction to iron homeostasis in P. aeruginosa is unknown. In this work we explore the repercussions of (i) deleting the bfrB gene, and (ii) perturbing the BfrB:Bfd interaction in P. aeruginosa cells by either deleting the bfd gene or by replacing the wild type bfrB gene with a L68A/E81A double mutant allele in the P. aeruginosa chromosome. The effects of the mutations were evaluated by following the accumulation of iron in BfrB, analyzing levels of free and total intracellular iron, and by characterizing the ensuing iron homeostasis dysregulation phenotypes. The results reveal that P. aeruginosa accumulate iron mainly in BfrB, and that the nutrient does not accumulate in FtnA to detectable levels, even after deletion of the bfrB gene. Perturbing the BfrB:Bfd interaction causes irreversible flow of iron into BfrB, which leads to the accumulation of unusable intracellular iron while severely depleting the levels of free intracellular iron, which drives the cells to an acute iron starvation response despite harboring “normal” levels of total intracellular iron. These results are discussed in the context of a dynamic equilibrium between free cytosolic Fe2+ and Fe3+ compartmentalized in BfrB, which functions as a buffer to oppose rapid changes of free cytosolic iron. Finally, we also show that P. aeruginosa cells utilize iron stored in BfrB for growth in iron-limiting conditions, and that the utilization of BfrB-iron requires a functional BfrB:Bfd interaction.

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“…Iron, an essential nutrient for pathogenic bacteria, can also stimulate the formation of reactive oxygen species via the Haber Weiss cycle, in which free iron catalyzes the conversion of hydrogen peroxide and superoxide to the highly toxic hydroxyl radical (1, 2). Consequently, free levels of iron in bacteria are tightly regulated to ensure sufficiency for metabolic needs, while preventing iron-induced oxidative toxicity.…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, free levels of iron in bacteria are tightly regulated to ensure sufficiency for metabolic needs, while preventing iron-induced oxidative toxicity. To maintain iron homeostasis, pathogens must balance the need to obtain iron from their host with careful management of intracellular iron levels, which includes storage of iron reserves for subsequent utilization when the nutrient becomes scarce (2, 3). Bacteria have evolved two types of protein for storing iron, ferritin (Ftn) and bacterioferritin (Bfr); the latter is unique to bacteria (2, 4).…”

Section: Introductionmentioning

confidence: 99%

Concerted Motions Networking Pores and Distant Ferroxidase Centers Enable Bacterioferritin Function and Iron Traffic

Yao¹,

Rui²,

Kumar³

et al. 2015

Biochemistry

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X-ray crystallography, molecular dynamics (MD) simulations and biochemistry were utilized to investigate the effect of introducing hydrophobic interactions in the 4-fold (N148L and Q151L) and B-pores (D34F) of Pseudomonas aeruginosa bacterioferritin B (BfrB) on BfrB function. The structures show only local structural perturbations and confirm the anticipated hydrophobic interactions. Surprisingly, structures obtained after soaking crystals in Fe2+-containing crystallization solution revealed that although iron loads into the ferroxidase centers of the mutants, the side chains of ferroxidase ligands E51 and H130 do not reorganize to bind the iron ions, as is seen in the wt BfrB structures. Similar experiments with a double mutant (C89S/K96C) prepared to introduce changes outside the pores show competent ferroxidase centers that function akin to those in wt BfrB. MD simulations comparing wt BfrB with the D34F and N148L mutants show that the mutants exhibit significantly reduced flexibility, and reveal a network of concerted motions linking ferroxidase centers and 4-fold and B-pores, which are important for imparting ferroxidase centers in BfrB with the required flexibility to function efficiently. In agreement, the efficiency of Fe2+ oxidation and uptake of the 4-fold and B-pore mutants in solution is significantly compromised relative to wt or C89S/K96C BfrB. Finally, our structures show a large number of previously unknown iron binding sites in the interior cavity and B-pores of BfrB, which reveal in unprecedented detail conduits followed by iron and phosphate ions across the BfrB shell, as well as paths in the interior cavity that may facilitate nucleation of the iron phosphate mineral.

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Control of Iron Metabolism in Bacteria

Cited by 48 publications

References 212 publications

Coordinate Regulation of the Suf and Isc Fe-S Cluster Biogenesis Pathways by IscR Is Essential for Viability of Escherichia coli

Coordinate Regulation of the Suf and Isc Fe-S Cluster Biogenesis Pathways by IscR Is Essential for Viability of Escherichia coli

Inhibiting the BfrB:Bfd interaction in Pseudomonas aeruginosa causes irreversible iron accumulation in bacterioferritin and iron deficiency in the bacterial cytosol

Concerted Motions Networking Pores and Distant Ferroxidase Centers Enable Bacterioferritin Function and Iron Traffic

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