naphthoquinones has been researched along with stigmatellin* in 3 studies
3 other study(ies) available for naphthoquinones and stigmatellin
Article | Year |
---|---|
Molecular basis for atovaquone binding to the cytochrome bc1 complex.
Atovaquone is a substituted 2-hydroxynaphthoquinone that is used therapeutically to treat Plasmodium falciparum malaria, Pneumocystis carinii pneumonia, and Toxoplasma gondii toxoplasmosis. It is thought to act on these organisms by inhibiting the cytochrome bc1 complex. We have examined the interaction of atovaquone with the bc1 complex isolated from Saccharomyces cerevisiae, a surrogate, nonpathogenic fungus. Atovaquone inhibits the bc1 complex competitively with apparent Ki = 9 nm, raises the midpoint potential of the Rieske iron-sulfur protein from 285 to 385 mV, and shifts the g values in the EPR spectrum of the Rieske center. These results indicate that atovaquone binds to the ubiquinol oxidation pocket of the bc1 complex, where it interacts with the Rieske iron-sulfur protein. A computed energy-minimized structure for atovaquone liganded to the yeast bc1 complex suggests that a phenylalanine at position 275 of cytochrome b in the bovine bc1 complex, as opposed to leucine at the equivalent position in the yeast enzyme, is responsible for the decreased sensitivity of the bovine bc1 complex (Ki = 80 nm) to atovaquone. When a L275F mutation was introduced into the yeast cytochrome b, the sensitivity of the yeast enzyme to atovaquone decreased (Ki = 100 nm) with no loss in activity, confirming that the L275F exchange contributes to the differential sensitivity of these two species to atovaquone. These results provide the first molecular description of how atovaquone binds to the bc1 complex and explain the differential inhibition of the fungal versus mammalian enzymes. Topics: Amino Acid Sequence; Anti-Bacterial Agents; Atovaquone; Binding Sites; Binding, Competitive; Electron Transport Complex III; Molecular Sequence Data; Naphthoquinones; Oxidation-Reduction; Polyenes; Protein Structure, Secondary; Protein Structure, Tertiary; Saccharomyces cerevisiae; Ubiquinone | 2003 |
Pneumocystis carinii synthesizes four ubiquinone homologs: inhibition by atovaquone and bupravaquone but not by stigmatellin.
Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Atovaquone; Female; Naphthoquinones; Oxidoreductases; Parabens; Pneumocystis; Polyenes; Rats; Ubiquinone | 2001 |
Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site.
Atovaquone is the major active component of the new antimalarial drug Malarone. Considerable evidence suggests that malaria parasites become resistant to atovaquone quickly if atovaquone is used as a sole agent. The mechanism by which the parasite develops resistance to atovaquone is not yet fully understood. Atovaquone has been shown to inhibit the cytochrome bc(1) (CYT bc(1)) complex of the electron transport chain of malaria parasites. Here we report point mutations in Plasmodium falciparum CYT b that are associated with atovaquone resistance. Single or double amino acid mutations were detected from parasites that originated from a cloned line and survived various concentrations of atovaquone in vitro. A single amino acid mutation was detected in parasites isolated from a recrudescent patient following atovaquone treatment. These mutations are associated with a 25- to 9,354-fold range reduction in parasite susceptibility to atovaquone. Molecular modeling showed that amino acid mutations associated with atovaquone resistance are clustered around a putative atovaquone-binding site. Mutations in these positions are consistent with a reduced binding affinity of atovaquone for malaria parasite CYT b. Topics: Amino Acid Sequence; Animals; Antimalarials; Atovaquone; Binding Sites; Cattle; Chickens; Conserved Sequence; Cytochrome b Group; Drug Resistance; Eukaryota; Methacrylates; Models, Molecular; Molecular Sequence Data; Mutation; Naphthoquinones; Plasmodium falciparum; Polyenes; Sequence Homology, Amino Acid; Thiazoles | 2000 |