ArticlePLoS genetics2016
Intracellular Zn(II) Intoxication Leads to Dysregulation of the PerR Regulon Resulting in Heme Toxicity in Bacillus subtilis.
Article in PLoS genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
45 citing papers in PubMed, 58 citations in OpenAlex.
- The genes zntA and zntR encoding a P-type ATPase and its activator confer zinc and cadmium resistance in Chromobacterium violaceum.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2026Article
- A review of the iron requirements and its determination in commercial poultry.Animal nutrition (Zhongguo xu mu shou yi xue hui) · 2026Review
- Zinc tolerance through glutathione import strikes a fine balance between protection and damage inMicrobiology (Reading, England) · 2026Article
- Zinc Tolerance Through Glutathione Import Strikes a Fine Balance Between Protection and Damage inbioRxiv : the preprint server for biology · 2026Article
- Operonic architecture of bacterial metal response: envelope constraints, evolutionary mobility, and bioremediation design rules.World journal of microbiology & biotechnology · 2026Review
- Microbial metal physiology: ions to ecosystems.Nature reviews. Microbiology · 2025Review
- c-di-GMP-Dependent Regulation of Motility bybioRxiv : the preprint server for biology · 2025Article
- A cytochromeApplied and environmental microbiology · 2025Article
- Metals in Motion: Understanding Labile Metal Pools in Bacteria.Biochemistry · 2025Review
- Metalation of Extracytoplasmic Proteins and Bacterial Cell Envelope Homeostasis.Annual review of microbiology · 2024Review
- TheJournal of bacteriology · 2024Article
- Activation of zinc uptake regulator by zinc binding to three regulatory sites.Nucleic acids research · 2024Article
- ThebioRxiv : the preprint server for biology · 2024Article
- Regulation of heme biosynthesis via the coproporphyrin dependent pathway in bacteria.Frontiers in microbiology · 2024Review
- Zinc excess impairsMicrobiology spectrum · 2023Article
- A bioinformatic analysis of zinc transporters in intestinal Lactobacillaceae.Metallomics : integrated biometal science · 2023Article
- A model industrial workhorse: Bacillus subtilis strain 168 and its genome after a quarter of a century.Microbial biotechnology · 2023Review
- Meddling with Metal Sensors: Fur-Family Proteins as Signaling Hubs.Journal of bacteriology · 2023Review
- Structural and Biochemical Characterization ofBiomolecules · 2023Article
- Bacterial metabolism and susceptibility to cell wall-active antibiotics.Advances in microbial physiology · 2023Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Transition metal ions (Zn(II), Cu(II)/(I), Fe(III)/(II), Mn(II)) are essential for life and participate in a wide range of biological functions. Cellular Zn(II) levels must be high enough to ensure that it can perform its essential roles. Yet, since Zn(II) binds to ligands with high avidity, excess Zn(II) can lead to protein mismetallation. The major targets of mismetallation, and the underlying causes of Zn(II) intoxication, are not well understood. Here, we use a forward genetic selection to identify targets of Zn(II) toxicity. In wild-type cells, in which Zn(II) efflux prevents intoxication of the cytoplasm, extracellular Zn(II) inhibits the electron transport chain due to the inactivation of the major aerobic cytochrome oxidase. This toxicity can be ameliorated by depression of an alternate oxidase or by mutations that restrict access of Zn(II) to the cell surface. Conversely, efflux deficient cells are sensitive to low levels of Zn(II) that do not inhibit the respiratory chain. Under these conditions, intracellular Zn(II) accumulates and leads to heme toxicity. Heme accumulation results from dysregulation of the regulon controlled by PerR, a metal-dependent repressor of peroxide stress genes. When metallated with Fe(II) or Mn(II), PerR represses both heme biosynthesis (hemAXCDBL operon) and the abundant heme protein catalase (katA). Metallation of PerR with Zn(II) disrupts this coordination, resulting in depression of heme biosynthesis but continued repression of catalase. Our results support a model in which excess heme partitions to the membrane and undergoes redox cycling catalyzed by reduced menaquinone thereby resulting in oxidative stress.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.