Mechanisms of nickel toxicity in microorganisms

Macomber, Lee; Hausinger, Robert P.

doi:10.1039/c1mt00063b

Cited by 292 publications

(199 citation statements)

References 170 publications

(271 reference statements)

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“…The enhancement of the negative impacts of cobalt and nickel by copper is not surprising; such interactions between toxic metals have been observed before (16,17). The mitigation of nickel toxicity by iron is also predictable: it supports previous research showing that nickel disrupts iron-containing enzymes and increases the expression of the iron uptake machinery in E. coli (38,39). Cu(II), like Ni(II), is known to interfere with iron-containing enzymes (15,40), which makes our finding that Fe(II) and Cu(II) interact synergistically to inhibit growth particularly interesting.…”

Section: Discussionsupporting

confidence: 70%

Iron and Copper Act Synergistically To Delay Anaerobic Growth of Bacteria

Bird

Coleman

Newman

2013

Appl Environ Microbiol

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bTransition metals are known to cause toxic effects through their interaction with oxygen, but toxicity under anoxic conditions is poorly understood. Here we investigated the effects of iron (Fe) and copper (Cu) on the anaerobic growth and gene expression of the purple phototrophic bacterium Rhodopseudomonas palustris TIE-1. We found that Fe(II) and Cu(II) act synergistically to delay anaerobic growth at environmentally relevant metal concentrations. Cu(I) and Cu(II) had similar effects both alone and in the presence of ascorbate, a Cu(II) reductant, indicating that reduction of Cu(II) to Cu(I) by Fe(II) is not sufficient to explain the growth inhibition. Addition of Cu(II) increased the toxicity of Co(II) and Ni(II); in contrast, Ni(II) toxicity was diminished in the presence of Fe(II). The synergistic anaerobic toxicity of Fe(II) and Cu(II) was also observed for Escherichia coli MG1655, Shewanella oneidensis MR-1, and Rhodobacter capsulatus SB1003. Gene expression analyses for R. palustris identified three regulatory genes that respond to Cu(II) and not to Fe(II): homologs of cueR and cusR, two known proteobacterial copper homeostasis regulators, and csoR, a copper regulator recently identified in Mycobacterium tuberculosis. Two P-type ATPase efflux pumps, along with an F o F 1 ATP synthase, were also upregulated by Cu(II) but not by Fe(II). An Escherichia coli mutant deficient in copA, cus, and cueO showed a smaller synergistic effect, indicating that iron might interfere with one or more of the copper homeostasis systems. Our results suggest that interactive effects of transition metals on microbial physiology may be widespread under anoxic conditions, although the molecular mechanisms remain to be more fully elucidated.

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Section: Discussionsupporting

confidence: 70%

Iron and Copper Act Synergistically To Delay Anaerobic Growth of Bacteria

Bird

Coleman

Newman

2013

Appl Environ Microbiol

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“…Using qRT-PCR, we tested the response of Rpal_4085 under anoxic conditions to the cations Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Ca(II), and hydrogen peroxide (H 2 O 2 ). With the exception of Zn(II) and Ca(II), these divalent metals are known to be redox active at physiological pH (19,(26)(27)(28)(29). We used H 2 O 2 as an oxidative stress-inducing control and Zn(II) and Ca(II) as nonredox active divalent metal controls.…”

Section: Mutant Analysismentioning

confidence: 99%

Nonredundant Roles for Cytochrome c ₂ and Two High-Potential Iron-Sulfur Proteins in the Photoferrotroph Rhodopseudomonas palustris TIE-1

et al. 2014

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eThe purple bacterium Rhodopseudomonas palustris TIE-1 expresses multiple small high-potential redox proteins during photoautotrophic growth, including two high-potential iron-sulfur proteins (HiPIPs) (PioC and Rpal_4085) and a cytochrome c 2 . We evaluated the role of these proteins in TIE-1 through genetic, physiological, and biochemical analyses. Deleting the gene encoding cytochrome c 2 resulted in a loss of photosynthetic ability by TIE-1, indicating that this protein cannot be replaced by either HiPIP in cyclic electron flow. PioC was previously implicated in photoferrotrophy, an unusual form of photosynthesis in which reducing power is provided through ferrous iron oxidation. Using cyclic voltammetry (CV), electron paramagnetic resonance (EPR) spectroscopy, and flash-induced spectrometry, we show that PioC has a midpoint potential of 450 mV, contains all the typical features of a HiPIP, and can reduce the reaction centers of membrane suspensions in a light-dependent manner at a much lower rate than cytochrome c 2 . These data support the hypothesis that PioC linearly transfers electrons from iron, while cytochrome c 2 is required for cyclic electron flow. Rpal_4085, despite having spectroscopic characteristics and a reduction potential similar to those of PioC, is unable to reduce the reaction center. Rpal_4085 is upregulated by the divalent metals Fe(II), Ni(II), and Co(II), suggesting that it might play a role in sensing or oxidizing metals in the periplasm. Taken together, our results suggest that these three small electron transfer proteins perform different functions in the cell.

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“…Excess iron (Fe) is harmful due to its participation in Fenton chemistry, which produces a highly reactive hydroxyl radical that can damage biomolecules (4-7). Other transition metals, including Mn, Zn, cobalt (Co), nickel (Ni), and copper (Cu), become toxic at high concentrations partly because they compete for each other's cognate metal-binding sites in enzymes (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Regardless of the mechanism of metal toxicity, bacteria have evolved ways to minimize the deleterious impact of metal ion excess.…”

mentioning

confidence: 99%

Functional Determinants of Metal Ion Transport and Selectivity in Paralogous Cation Diffusion Facilitator Transporters CzcD and MntE in Streptococcus pneumoniae

Martin

Giedroc

2016

J Bacteriol

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Cation diffusion facilitators (CDFs) are a large family of divalent metal transporters that collectively possess broad metal specificity and contribute to intracellular metal homeostasis and virulence in bacterial pathogens. Streptococcus pneumoniae expresses two homologous CDF efflux transporters, MntE and CzcD. Cells lacking mntE or czcD are sensitive to manganese (Mn) or zinc (Zn) toxicity, respectively, and specifically accumulate Mn or Zn, respectively, thus suggesting that MntE selectively transports Mn, while CzcD transports Zn. Here, we probe the origin of this metal specificity using a phenotypic growth analysis of pneumococcal variants. Structural homology to Escherichia coli YiiP predicts that both MntE and CzcD are dimeric and each protomer harbors four pairs of conserved metal-binding sites, termed the A site, the B site, and the C1/C2 binuclear site. We find that single amino acid mutations within both the transmembrane domain A site and the B site in both CDFs result in a cellular metal sensitivity similar to that of the corresponding null mutants. However, multiple mutations in the predicted cytoplasmic C1/C2 cluster of MntE have no impact on cellular Mn resistance, in contrast to the analogous substitutions in CzcD, which do have on impact on cellular Zn resistance. Deletion of the MntE-specific C-terminal tail, present only in Mn-specific bacterial CDFs, resulted in only a modest growth phenotype. Further analysis of MntE-CzcD functional chimeric transporters showed that Asn and Asp in the ND-DD A-site motif of MntE and the most N-terminal His in the HD-HD site A of CzcD (the specified amino acids are underlined) play key roles in transporter metal selectivity. IMPORTANCECation diffusion facilitator (CDF) proteins are divalent metal ion transporters that are conserved in organisms ranging from bacteria to humans and that play important roles in cellular physiology, from metal homeostasis and resistance to type I diabetes in vertebrates. The respiratory pathogen Streptococcus pneumoniae expresses two metal CDF transporters, CzcD and MntE. How CDFs achieve metal selectivity is unclear. We show here that CzcD and MntE are true paralogs, as CzcD transports zinc, while MntE selectively transports manganese. Through the use of an extensive collection of pneumococcal variants, we show that a primary determinant for metal selectivity is the A site within the transmembrane domain. This extends our understanding of how CDFs discriminate among transition metals. T ransition metals from manganese (Mn) to zinc (Zn) in the first row of the periodic table serve as essential cofactors in metalloenzymes that are required for many important cellular processes, including replication, regulation, and central metabolism, among all domains of life (1-3). Despite their importance, excess transition metals can impair bacterial growth. Excess iron (Fe) is harmful due to its participation in Fenton chemistry, which produces a highly reactive hydroxyl radical that can damage biomolecules (4-7). Other transition m...

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Mechanisms of nickel toxicity in microorganisms

Cited by 292 publications

References 170 publications

Iron and Copper Act Synergistically To Delay Anaerobic Growth of Bacteria

Iron and Copper Act Synergistically To Delay Anaerobic Growth of Bacteria

Nonredundant Roles for Cytochrome c ₂ and Two High-Potential Iron-Sulfur Proteins in the Photoferrotroph Rhodopseudomonas palustris TIE-1

Functional Determinants of Metal Ion Transport and Selectivity in Paralogous Cation Diffusion Facilitator Transporters CzcD and MntE in Streptococcus pneumoniae

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Mechanisms of nickel toxicity in microorganisms

Cited by 292 publications

References 170 publications

Iron and Copper Act Synergistically To Delay Anaerobic Growth of Bacteria

Iron and Copper Act Synergistically To Delay Anaerobic Growth of Bacteria

Nonredundant Roles for Cytochrome c 2 and Two High-Potential Iron-Sulfur Proteins in the Photoferrotroph Rhodopseudomonas palustris TIE-1

Functional Determinants of Metal Ion Transport and Selectivity in Paralogous Cation Diffusion Facilitator Transporters CzcD and MntE in Streptococcus pneumoniae

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Nonredundant Roles for Cytochrome c ₂ and Two High-Potential Iron-Sulfur Proteins in the Photoferrotroph Rhodopseudomonas palustris TIE-1