ArticleThe Journal of biological chemistry2012
Inhibitors of V-ATPase proton transport reveal uncoupling functions of tether linking cytosolic and membrane domains of V0 subunit a (Vph1p).
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 1 of them a synthesis that pooled it.
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Who cites it
30 citing papers in PubMed, 1 synthesis or guideline pooled it, 59 citations in OpenAlex.
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- Thonzonium bromide inhibits progression of malignant pleural mesothelioma through regulation of ERK1/2 and p38 pathways and mitochondrial uncoupling.Cancer cell international · 2024Article
- Endosomal Acid-Base Homeostasis in Neurodegenerative Diseases.Reviews of physiology, biochemistry and pharmacology · 2023Article
- Genome-wide CRISPR screen reveals v-ATPase as a drug target to lower levels of ALS protein ataxin-2.Cell reports · 2022Article
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- Phosphatase inhibitors BVT-948 and alexidine dihydrochloride inhibit sexual development of the malaria parasite Plasmodium berghei.International journal for parasitology. Drugs and drug resistance · 2022Article
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- Identification of small molecules that disrupt vacuolar function in the pathogen Candida albicans.PloS one · 2017Article
- Regulation of Vacuolar H+-ATPase (V-ATPase) Reassembly by Glycolysis Flow in 6-Phosphofructo-1-kinase (PFK-1)-deficient Yeast Cells.The Journal of biological chemistry · 2016Article
- Anticandidal Effect and Mechanisms of Monoterpenoid, Perillyl Alcohol against Candida albicans.PloS one · 2016Article
- Perturbation of the Vacuolar ATPase: A NOVEL CONSEQUENCE OF INOSITOL DEPLETION.The Journal of biological chemistry · 2015Article
- Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library.Antibiotics (Basel, Switzerland) · 2015Article
- Cloning, expression and purification of subunit H of vacuolar H⁺-ATPase from Mythimna separata Walker (Lepidoptera: Noctuidae).International journal of molecular sciences · 2014Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Vacuolar ATPases (V-ATPases) are important for many cellular processes, as they regulate pH by pumping cytosolic protons into intracellular organelles. The cytoplasm is acidified when V-ATPase is inhibited; thus we conducted a high-throughput screen of a chemical library to search for compounds that acidify the yeast cytosol in vivo using pHluorin-based flow cytometry. Two inhibitors, alexidine dihydrochloride (EC(50) = 39 μM) and thonzonium bromide (EC(50) = 69 μM), prevented ATP-dependent proton transport in purified vacuolar membranes. They acidified the yeast cytosol and caused pH-sensitive growth defects typical of V-ATPase mutants (vma phenotype). At concentrations greater than 10 μM the inhibitors were cytotoxic, even at the permissive pH (pH 5.0). Membrane fractions treated with alexidine dihydrochloride and thonzonium bromide fully retained concanamycin A-sensitive ATPase activity despite the fact that proton translocation was inhibited by 80-90%, indicating that V-ATPases were uncoupled. Mutant V-ATPase membranes lacking residues 362-407 of the tether of Vph1p subunit a of V(0) were resistant to thonzonium bromide but not to alexidine dihydrochloride, suggesting that this conserved sequence confers uncoupling potential to V(1)V(0) complexes and that alexidine dihydrochloride uncouples the enzyme by a different mechanism. The inhibitors also uncoupled the Candida albicans enzyme and prevented cell growth, showing further specificity for V-ATPases. Thus, a new class of V-ATPase inhibitors (uncouplers), which are not simply ionophores, provided new insights into the enzyme mechanism and original evidence supporting the hypothesis that V-ATPases may not be optimally coupled in vivo. The consequences of uncoupling V-ATPases in vivo as potential drug targets are discussed.
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Registered trials
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