Cytochrome b Mutations That Modify the Ubiquinol-binding Pocket of the Cytochrome bc1 Complex and Confer Anti-malarial Drug Resistance in Saccharomyces cerevisiae

• Published in: The Journal of biological chemistry Vol. 280; no. 17; pp. 17142 - 17148
• Main Authors: Kessl, Jacques J., Ha, Kevin H., Merritt, Anne K., Lange, Benjamin B., Hill, Philip, Meunier, Brigitte, Meshnick, Steven R., Trumpower, Bernard L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.04.2005; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Sequence; Animals; Antimalarials - pharmacology; Atovaquone; Cytochromes b - genetics; Dose-Response Relationship, Drug; Electron Transport Complex III - chemistry; Electron Transport Complex III - metabolism; Inhibitory Concentration 50; Kinetics; Malaria - metabolism; Models, Molecular; Molecular Sequence Data; Mutation; Naphthoquinones - chemistry; Naphthoquinones - pharmacology; Oxygen Consumption; Plasmodium falciparum - genetics; Plasmodium falciparum - metabolism; Point Mutation; Protein Binding; Saccharomyces cerevisiae - genetics; Sequence Homology, Amino Acid; Time Factors; Ubiquinone - analogs & derivatives; Ubiquinone - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M500388200

Atovaquone is a new anti-malarial agent that specifically targets the cytochrome bc1 complex and inhibits parasite respiration. A growing number of failures of this drug in the treatment of malaria have been genetically linked to point mutations in the mitochondrial cytochrome b gene. To better understand the molecular basis of atovaquone resistance in malaria, we introduced five of these mutations, including the most prevalent variant found in Plasmodium falciparum (Y268S), into the cytochrome b gene of the budding yeast Saccharomyces cerevisiae and thus obtained cytochrome bc1 complexes resistant to inhibition by atovaquone. By modeling the variations in cytochrome b structure and atovaquone binding with the mutated bc1 complexes, we obtained the first quantitative explanation for the molecular basis of atovaquone resistance in malaria parasites.