| Abstract | Atovaquone is a substituted hydroxynaphthoquinone that is widely used to prevent and clear Plasmodium falciparum malaria and Pneumocystis jirovecii pneumonia. Atovaquone inhibits respiration in target organisms by specifically binding to the ubiquinol oxidation site at center P of the cytochrome bc(1) complex. The failure of atovaquone treatment and mortality of patients with malaria and P. jirovecii pneumonia has been linked to the appearance of mutations in the cytochrome b gene. To better understand the molecular basis of atovaquone resistance, we have introduced seven of the mutations from atovaquone-resistant P. jirovecii into the cytochrome b gene of Saccharomyces cerevisiae and thus obtained cytochrome bc(1) complexes resistant to inhibition by atovaquone. In these enzymes, the IC(50) for atovaquone increases from 25 nm for the enzyme from wild-type yeast to >500 nm for some of the mutated enzymes. Modeling of the changes in cytochrome b structure and atovaquone binding with the mutated bc(1) complexes provides the first quantitative explanation for the molecular basis of atovaquone resistance. |
| Authors | Jacques J Kessl, Philip Hill, Benjamin B Lange, Steven R Meshnick, Brigitte Meunier, Bernard L Trumpower
(Affiliation: Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.)
|
| Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 279
Issue 4
Pg. 2817-24
(Jan 23 2004)
ISSN: 0021-9258 United States |
| PMID | 14576156
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
|
| Chemical References |
- Antifungal Agents
- Naphthoquinones
- Atovaquone
- Electron Transport Complex III
|
| Topics |
- Amino Acid Sequence
- Antifungal Agents
(metabolism, pharmacology)
- Atovaquone
- Binding Sites
(genetics)
- Drug Resistance, Fungal
(genetics)
- Electron Transport Complex III
(genetics, metabolism)
- Models, Molecular
- Molecular Sequence Data
- Mutation
- Naphthoquinones
(metabolism, pharmacology)
- Pneumocystis jirovecii
(drug effects, genetics)
- Protein Binding
- Protein Conformation
- Saccharomyces cerevisiae
(genetics)
|
