ArticlePLoS biology2007
Nitroimidazole action in Entamoeba histolytica: a central role for thioredoxin reductase.
Article in PLoS biology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers, 1 of them a synthesis that pooled it.
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Who cites it
64 citing papers in PubMed, 1 synthesis or guideline pooled it, 148 citations in OpenAlex.
- A systematic review of anti-Parasitology · 2021Pooled it
- Metronidazole and ether derivatives target Helicobacter pylori via simultaneous stress induction and inhibition.Nature microbiology · 2026Article
- Metronidazole Activation by a Deeply Entangled Dimeric Malic Enzyme inPathogens (Basel, Switzerland) · 2025Article
- Identification and characterization of archaeal-type FAD synthase as a novel tractable drug target from the parasitic protozoamSphere · 2024Article
- Proteomics-Based RT-qPCR and Functional Analysis of 18 Genes in Metronidazole Resistance ofAntibiotics (Basel, Switzerland) · 2024Article
- In Vitro Evaluation of the Antiamoebic Activity of Kaempferol against Trophozoites ofInternational journal of molecular sciences · 2023Article
- Riluzole, a Derivative of Benzothiazole as a Potential Anti-Amoebic Agent againstPharmaceuticals (Basel, Switzerland) · 2023Article
- Genome-Wide Libraries for Protozoan Pathogen Drug Target Screening Using Yeast Surface Display.ACS infectious diseases · 2023Article
- Review
- Attenuation of In Vitro and In Vivo Virulence Is Associated with Repression of Gene Expression of AIG1 Gene inPathogens (Basel, Switzerland) · 2023Article
- Mass Spectrometry-Based Metabolomics Revealed Effects of Metronidazole onPharmaceuticals (Basel, Switzerland) · 2023Article
- Evaluation of intestinal parasites as a causative agent of diarrhea in children and some treatments used in Babylon Governorate.The Pan African medical journal · 2023Article
- Antigiardial Activity ofPlants (Basel, Switzerland) · 2022Article
- Cellular mechanism of action of 2-nitroimidazoles as hypoxia-selective therapeutic agents.Redox biology · 2022Article
- Ponatinib, Lestaurtinib, and mTOR/PI3K Inhibitors Are Promising Repurposing Candidates against Entamoeba histolytica.Antimicrobial agents and chemotherapy · 2022Article
- Article
- A reassessment of the role of oxygen scavenging enzymes in the emergence of metronidazole resistance in trichomonads.International journal for parasitology. Drugs and drug resistance · 2021Article
- Identification of proteins and cellular pathways targeted by 2-nitroimidazole hypoxic cytotoxins.Redox biology · 2021Article
- An unusual thioredoxin system in the facultative parasite Acanthamoeba castellanii.Cellular and molecular life sciences : CMLS · 2021Article
- 2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche.Communications biology · 2020Article
4 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Metronidazole, a 5-nitroimidazole drug, has been the gold standard for several decades in the treatment of infections with microaerophilic protist parasites, including Entamoeba histolytica. For activation, the drug must be chemically reduced, but little is known about the targets of the active metabolites. Applying two-dimensional gel electrophoresis and mass spectrometry, we searched for protein targets in E. histolytica. Of all proteins visualized, only five were found to form adducts with metronidazole metabolites: thioredoxin, thioredoxin reductase, superoxide dismutase, purine nucleoside phosphorylase, and a previously unknown protein. Recombinant thioredoxin reductase carrying the modification displayed reduced enzymatic activity. In treated cells, essential non-protein thiols such as free cysteine were also affected by covalent adduct formation, their levels being drastically reduced. Accordingly, addition of cysteine allowed E. histolytica to survive in the presence of otherwise lethal metronidazole concentrations and reduced protein adduct formation. Finally, we discovered that thioredoxin reductase reduces metronidazole and other nitro compounds, suggesting a new model of metronidazole activation in E. histolytica with a central role for thioredoxin reductase. By reducing metronidazole, the enzyme renders itself and associated thiol-containing proteins vulnerable to adduct formation. Because thioredoxin reductase is a ubiquitous enzyme, similar processes could occur in other eukaryotic or prokaryotic organisms.
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Registered trials
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