ArticleThe Journal of biological chemistry2005
Uncovering the molecular mode of action of the antimalarial drug atovaquone using a bacterial system.
Article in The Journal of biological chemistry, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
What it found
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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
41 citing papers in PubMed, 95 citations in OpenAlex.
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- A review on molecular markers ofJournal of parasitic diseases : official organ of the Indian Society for Parasitology · 2025Review
- Fighting Cancer with Photodynamic Therapy and Nanotechnologies: Current Challenges and Future Directions.International journal of molecular sciences · 2025Review
- Atovaquone enhances antitumor efficacy of TCR-T therapy by augmentation of ROS-induced ferroptosis in hepatocellular carcinoma.Cancer immunology, immunotherapy : CII · 2024Article
- Metabolic vulnerability of cancer stem cells and their niche.Frontiers in pharmacology · 2024Review
- Unique Properties of Apicomplexan Mitochondria.Annual review of microbiology · 2023Review
- Oxidative phosphorylation inhibitors inhibit proliferation of endometriosis cells.Reproduction (Cambridge, England) · 2023Article
- Parasite powerhouse: A review of the Toxoplasma gondii mitochondrion.The Journal of eukaryotic microbiology · 2022Review
- Prevention of Tumor Growth and Dissemination by In Situ Vaccination with Mitochondria-Targeted Atovaquone.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- Decoding the Molecular Effects of Atovaquone Linked Resistant Mutations onInternational journal of molecular sciences · 2021Article
- Insights on recent approaches in drug discovery strategies and untapped drug targets against drug resistance.Future journal of pharmaceutical sciences · 2021Review
- Drug rechanneling: A novel paradigm for cancer treatment.Seminars in cancer biology · 2021Review
- Why All the Fuss about Oxidative Phosphorylation (OXPHOS)?Journal of medicinal chemistry · 2020Review
- New Trends for Antimalarial Drugs: Synergism between Antineoplastics and Antimalarials on Breast Cancer Cells.Biomolecules · 2020Article
- Article
- Anti-malarial atovaquone exhibits anti-tumor effects by inducing DNA damage in hepatocellular carcinoma.American journal of cancer research · 2018Article
- Pyrimidine Pathway-Dependent and -Independent Functions of the Toxoplasma gondii Mitochondrial Dihydroorotate Dehydrogenase.Infection and immunity · 2016Article
- Human Mitochondrial Cytochrome b Variants Studied in Yeast: Not All Are Silent Polymorphisms.Human mutation · 2016Article
- Crystal structure of truncated aspartate transcarbamoylase from Plasmodium falciparum.Acta crystallographica. Section F, Structural biology communications · 2016Article
- Repurposing atovaquone: targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells.Oncotarget · 2016Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Atovaquone is an antiparasitic drug that selectively inhibits electron transport through the parasite mitochondrial cytochrome bc1 complex and collapses the mitochondrial membrane potential at concentrations far lower than those at which the mammalian system is affected. Because this molecule represents a new class of antimicrobial agents, we seek a deeper understanding of its mode of action. To that end, we employed site-directed mutagenesis of a bacterial cytochrome b, combined with biophysical and biochemical measurements. A large scale domain movement involving the iron-sulfur protein subunit is required for electron transfer from cytochrome b-bound ubihydroquinone to cytochrome c1 of the cytochrome bc1 complex. Here, we show that atovaquone blocks this domain movement by locking the iron-sulfur subunit in its cytochrome b-binding conformation. Based on our malaria atovaquone resistance data, a series of cytochrome b mutants was produced that were predicted to have either enhanced or reduced sensitivity to atovaquone. Mutations altering the bacterial cytochrome b at its ef loop to more closely resemble Plasmodium cytochrome b increased the sensitivity of the cytochrome bc1 complex to atovaquone. A mutation within the ef loop that is associated with resistant malaria parasites rendered the complex resistant to atovaquone, thereby providing direct proof that the mutation causes atovaquone resistance. This mutation resulted in a 10-fold reduction in the in vitro activity of the cytochrome bc1 complex, suggesting that it may exert a cost on efficiency of the cytochrome bc1 complex.
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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.