Mononuclear Iron Enzymes Are Primary Targets of Hydrogen Peroxide Stress

Anjem, Adil; Imlay, James A.

doi:10.1074/jbc.m111.330365

Cited by 195 publications

(231 citation statements)

References 60 publications

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“…Since in Mn salen, chelated metal is weakly held (65), the growth stimulation could be due to Mn ions that dissociate from the ligands. It has been suggested that the protective action of Mn chelates could result from the facilitated import of Mn, which forms intracellular Mn complexes possessing SOD-like activity (1,6,7,10) and replaces the Fe in Fe-containing enzymes (5). The facilitated Mn transport may explain the beneficial effects of those SOD mimics that have low metal/ligand stability such as Mn salen and MnBr 8 TSPP 3 -.…”

Section: The Strategies For Decreasing the Mnp Toxicitymentioning

confidence: 99%

Simple Biological Systems for Assessing the Activity of Superoxide Dismutase Mimics

Tovmasyan

Rebouças

Benov

2014

Antioxidants & Redox Signaling

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Significance: Half a century of research provided unambiguous proof that superoxide and species derived from it-reactive oxygen species (ROS)-play a central role in many diseases and degenerative processes. This stimulated the search for pharmaceutical agents that are capable of preventing oxidative damage, and methods of assessing their therapeutic potential. Recent Advances: The limitations of superoxide dismutase (SOD) as a therapeutic tool directed attention to small molecules, SOD mimics, that are capable of catalytically scavenging superoxide. Several groups of compounds, based on either metal complexes, including metalloporphyrins, metallocorroles, Mn(II) cyclic polyamines, and Mn(III) salen derivatives, or non-metal based compounds, such as fullerenes, nitrones, and nitroxides, have been developed and studied in vitro and in vivo. Very few entered clinical trials. Critical Issues and Future Directions: Development of SOD mimics requires in-depth understanding of their mechanisms of biological action. Elucidation of both molecular features, essential for efficient ROS-scavenging in vivo, and factors limiting the potential side effects requires biologically relevant and, at the same time, relatively simple testing systems. This review discuses the advantages and limitations of genetically engineered SOD-deficient unicellular organisms, Escherichia coli and Saccharomyces cerevisiae as tools for investigating the efficacy and mechanisms of biological actions of SOD mimics. These simple systems allow the scrutiny of the minimal requirements for a functional SOD mimic: the association of a high catalytic activity for superoxide dismutation, low toxicity, and an efficient cellular uptake/biodistribution. Antioxid. Redox Signal. 20, 2416Signal. 20, -2436

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Section: The Strategies For Decreasing the Mnp Toxicitymentioning

confidence: 99%

Simple Biological Systems for Assessing the Activity of Superoxide Dismutase Mimics

Tovmasyan

Rebouças

Benov

2014

Antioxidants & Redox Signaling

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“…In recent times, Mn has gained great attention for its role in oxidative stress and Fe starvation (5)(6)(7)(8). Oxidative stress stimulates the influx of Mn, leading to activation of Mn-dependent superoxide dismutase (SodA) to combat the pool of cytoplasmic superoxide radicals (5).…”

mentioning

confidence: 99%

“…Furthermore, Mn is also able to replace Fe from at least four nonredox Fe enzymes, viz. ribulose-5-phosphate-3-epimerase, peptide deformylase, threonine dehydrogenase, and cytosine deaminase (6,7). Such a replacement of the Fe atom by nonoxidizable Mn restores the functions of these enzymes when Escherichia coli is under oxidative stress (6,7).…”

mentioning

confidence: 99%

“…ribulose-5-phosphate-3-epimerase, peptide deformylase, threonine dehydrogenase, and cytosine deaminase (6,7). Such a replacement of the Fe atom by nonoxidizable Mn restores the functions of these enzymes when Escherichia coli is under oxidative stress (6,7). An alternative Mn-dependent ribonucleotide reductase (NrdEF) ensures chromosome replication when the Fe-dependent ribonucleotide reductase (NrdAB) is nonfunctional under Fe starvation in E. coli (8).…”

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confidence: 99%

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Novel MntR-Independent Mechanism of Manganese Homeostasis in Escherichia coli by the Ribosome-Associated Protein HflX

et al. 2014

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Manganese is a micronutrient required for activities of several important enzymes under conditions of oxidative stress and iron starvation. In Escherichia coli, the manganese homeostasis network primarily constitutes a manganese importer (MntH) and an exporter (MntP), which are regulated by the MntR dual regulator. In this study, we find that deletion of E. coli hflX, which encodes a ribosome-associated GTPase with unknown function, renders extreme manganese sensitivity characterized by arrested cell growth, filamentation, lower rate of replication, and DNA damage. We demonstrate that perturbation by manganese induces unprecedented influx of manganese in ⌬hflX cells compared to that in the wild-type E. coli strain. Interestingly, our study indicates that the imbalance in manganese homeostasis in the ⌬hflX strain is independent of the MntR regulon. Moreover, the influx of manganese leads to a simultaneous influx of zinc and inhibition of iron import in ⌬hflX cells. In order to review a possible link of HflX with the phage life cycle, we performed a lysis-lysogeny assay to show that the Mn-perturbed ⌬hflX strain reduces the frequency of lysogenization of the phage. This observation raises the possibility that the induced zinc influx in the manganese-perturbed ⌬hflX strain stimulates the activity of the zinc-metalloprotease HflB, the key determinant of the lysis-lysogeny switch. Finally, we propose that manganese-mediated autophosphorylation of HflX plays a central role in manganese, zinc, and iron homeostasis in E. coli cells.

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“…Manganese does not react with H2O2 and is capable of substituting for iron in several proteins which use iron as a cofactor (Anjem and Imlay, 2012). Using manganese as an alternative cofactor, we believe these proteins may be protected from inactivation.…”

Section: Discussionmentioning

confidence: 96%

The Role of Divalent Metals in DNA Replication During Periods of Oxidative Stress

Hutfilz¹,

Courcelle²,

Courcelle³

et al.

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Mononuclear Iron Enzymes Are Primary Targets of Hydrogen Peroxide Stress

Cited by 195 publications

References 60 publications

Simple Biological Systems for Assessing the Activity of Superoxide Dismutase Mimics

Simple Biological Systems for Assessing the Activity of Superoxide Dismutase Mimics

Novel MntR-Independent Mechanism of Manganese Homeostasis in Escherichia coli by the Ribosome-Associated Protein HflX

The Role of Divalent Metals in DNA Replication During Periods of Oxidative Stress

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