ArticleThe Journal of biological chemistry2014
Structural basis for inactivation of Giardia lamblia carbamate kinase by disulfiram.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 61 citations in OpenAlex.
- Metabolic flux analysis revealed key roles of ArcB in ADI pathway and IlvC in BCAA biosynthesis duringVirulence · 2026Article
- In Vivo Trypanocidal Activity of the Drug Disulfiram Combined with Benznidazole.ACS infectious diseases · 2026Article
- Review
- Disulfiram induces redox imbalance and perturbations in central glucose catabolism and metal homeostasis to inhibit the growth of Staphylococcus aureus.Scientific reports · 2025Article
- Disulfiram in liver diseases: a double-edged sword.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Remediation of multifarious metal ions and molecular docking assessment for pathogenic microbe disinfection in aqueous solution by waste-derived Ca-MOF.Environmental science and pollution research international · 2024Article
- The Use of Natural Bioactive Nutraceuticals in the Management of Tick-Borne Illnesses.Microorganisms · 2023Review
- Disulfiram: Mechanisms, Applications, and Challenges.Antibiotics (Basel, Switzerland) · 2023Review
- Antigiardial Activity of Novel Guanidine Compounds.ChemMedChem · 2022Article
- Reactivity and binding mode of disulfiram, its metabolites, and derivatives in SARS-CoV-2 PLJournal of molecular modeling · 2022Article
- Disulfiram: A Repurposed Drug in Preclinical and Clinical Development for the Treatment of Infectious Diseases.Anti-infective agents · 2022Article
- Validation and invalidation of SARS-CoV-2 main protease inhibitors using the Flip-GFP and Protease-Glo luciferase assays.Acta pharmaceutica Sinica. B · 2022Article
- Disulfiram blocked cell entry of SARS-CoV-2 via inhibiting the interaction of spike protein and ACE2.American journal of cancer research · 2022Article
- High-Throughput Fluorescent Assay for Inhibitor Screening of Proteases from RNA Viruses.Molecules (Basel, Switzerland) · 2021Article
- FDA-approved thiol-reacting drugs that potentially bind into the SARS-CoV-2 main protease, essential for viral replication.Journal of biomolecular structure & dynamics · 2021Article
- Therapeutic approaches against coronaviruses acute respiratory syndrome.Pharmacology research & perspectives · 2021Review
- Giardia duodenalis Virulence - "To Be, or Not To Be".Current tropical medicine reports · 2021Review
- Drug Repurposing of the Alcohol Abuse Medication Disulfiram as an Anti-Parasitic Agent.Frontiers in cellular and infection microbiology · 2021Article
- Ebselen, Disulfiram, Carmofur, PX-12, Tideglusib, and Shikonin Are Nonspecific Promiscuous SARS-CoV-2 Main Protease Inhibitors.ACS pharmacology & translational science · 2020Article
- COVID-19 therapy: What weapons do we bring into battle?Bioorganic & medicinal chemistry · 2020Article
Corrections and comments
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Authors and funding
7 authors at 5 institutions in 1 country.
Funding
Abstract
Carbamate kinase from Giardia lamblia is an essential enzyme for the survival of the organism. The enzyme catalyzes the final step in the arginine dihydrolase pathway converting ADP and carbamoyl phosphate to ATP and carbamate. We previously reported that disulfiram, a drug used to treat chronic alcoholism, inhibits G. lamblia CK and kills G. lamblia trophozoites in vitro at submicromolar IC50 values. Here, we examine the structural basis for G. lamblia CK inhibition of disulfiram and its analog, thiram, their activities against both metronidazole-susceptible and metronidazole-resistant G. lamblia isolates, and their efficacy in a mouse model of giardiasis. The crystal structure of G. lamblia CK soaked with disulfiram revealed that the compound thiocarbamoylated Cys-242, a residue located at the edge of the active site. The modified Cys-242 prevents a conformational transition of a loop adjacent to the ADP/ATP binding site, which is required for the stacking of Tyr-245 side chain against the adenine moiety, an interaction seen in the structure of G. lamblia CK in complex with AMP-PNP. Mass spectrometry coupled with trypsin digestion confirmed the selective covalent thiocarbamoylation of Cys-242 in solution. The Giardia viability studies in the metronidazole-resistant strain and the G. lamblia CK irreversible inactivation mechanism show that the thiuram compounds can circumvent the resistance mechanism that renders metronidazole ineffectiveness in drug resistance cases of giardiasis. Together, the studies suggest that G. lamblia CK is an attractive drug target for development of novel antigiardial therapies and that disulfiram, an FDA-approved drug, is a promising candidate for drug repurposing.
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