ArticleJournal of structural biology2016
X-ray structures of thioredoxin and thioredoxin reductase from Entamoeba histolytica and prevailing hypothesis of the mechanism of Auranofin action.
Article in Journal of structural biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed.
- Crosstalk of thioredoxin system and programmed cell death: from pathophysiology to novel therapy.Redox biology · 2026Review
- Novel Thiazolylimidazole Hybrids as Promising Antileishmanial Agents: Rational Design and Biological Evaluation.Pathogens (Basel, Switzerland) · 2026Article
- The Auranofin-Colistin Combination Efficiency Against the Gram-Negative Strains: A Review.Infection and drug resistance · 2026Review
- Beyond gold: the chemoenhancing mechanism and therapeutic potential of auranofin in melanoma.Cancer biology & medicine · 2025Article
- Metal-Based Approaches for the Fight against Antimicrobial Resistance: Mechanisms, Opportunities, and Challenges.Journal of the American Chemical Society · 2025Review
- The Many Lives of Auranofin: How an Old Anti-Rheumatic Agent May Become a Promising Antimicrobial Drug.Antibiotics (Basel, Switzerland) · 2024Review
- Auranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes.Nature communications · 2023Article
- Next Generation Gold Drugs and Probes: Chemistry and Biomedical Applications.Chemical reviews · 2023Review
- Review
- Gold complex compounds that inhibit drug-resistantFrontiers in antibiotics · 2023Article
- A Broad Spectrum Antiparasitic Activity of Organotin (IV) Derivatives and Its Untargeted Proteomic Profiling UsingPathogens (Basel, Switzerland) · 2022Article
- Evaluation of Auranofin Loading within Ferritin Nanocages.International journal of molecular sciences · 2022Article
- A Review: Natural and Synthetic Compounds TargetingMembranes · 2022Review
- Selenium and protozoan parasitic infections: selenocompounds and selenoproteins potential.Parasitology research · 2022Review
- Repurposing auranofin for treatment of Experimental Cerebral Toxoplasmosis.Acta parasitologica · 2021Article
- Article
- Gold(I) Phosphine Derivatives with Improved Selectivity as Topically Active Drug Leads to Overcome 5-Nitroheterocyclic Drug Resistance inJournal of medicinal chemistry · 2021Article
- Guided Antitumoural Drugs: (Imidazol-2-ylidene)(L)gold(I) Complexes Seeking Cellular Targets Controlled by the Nature of Ligand L.Chemistry (Weinheim an der Bergstrasse, Germany) · 2021Article
- Auranofin Resistance inFrontiers in cellular and infection microbiology · 2021Article
- Thioredoxin Reductase Is a Valid Target for Antimicrobial Therapeutic Development Against Gram-Positive Bacteria.Frontiers in microbiology · 2021Article
Corrections and comments
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Authors and funding
9 authors.
Funding
Abstract
The anti-arthritic gold-containing drug Auranofin is lethal to the protozoan intestinal parasite Entamoeba histolytica, the causative agent of human amebiasis, in both culture and animal models of the disease. A putative mechanism of Auranofin action proposes that monovalent gold, Au(I), released from the drug, can bind to the redox-active dithiol group of thioredoxin reductase (TrxR). Au(I) binding in the active site is expected to prevent electron transfer to the downstream substrate thioredoxin (Trx), thus interfering with redox homeostasis in the parasite. To clarify the molecular mechanism of Auranofin action in more detail, we determined a series of atomic resolution X-ray structures for E. histolytica thioredoxin (EhTrx) and thioredoxin reductase (EhTrxR), the latter with and without Auranofin. Only the disulfide-bonded form of the active site dithiol (Cys(140)-Cys(143)) was invariably observed in crystals of EhTrxR in spite of the addition of reductants in various crystallization trials, and no gold was found associated with these cysteines. Non-catalytic Cys(286) was identified as the only site of modification, but further mutagenesis studies using the C286Q mutant demonstrated that this site was not responsible for inhibition of EhTrxR by Auranofin. Interestingly, we obtained both of the catalytically-relevant conformations of this bacterial-like, low molecular weight TrxR in crystals without requiring an engineered disulfide linkage between Cys mutants of TrxR and Trx (as was originally done with Escherichia coli TrxR and Trx). We note that the -CXXC- catalytic motif, even if reduced, would likely not provide space sufficient to bind Au(I) by both cysteines of the dithiol group.
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