Journal article
Uncovering the Molecular Mode of Action of the Antimalarial Drug Atovaquone Using a Bacterial System
The Journal of biological chemistry, v 280(29), pp 27458-27465
22 Jul 2005
PMID: 15917236
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Atovaquone is an antiparasitic drug that selectively inhibits electron transport through the parasite mitochondrial cytochrome
bc
1
complex and collapses the mitochondrial membrane potential at concentrations far lower than those at which the mammalian system is affected. Because this molecule represents a new class of antimicrobial agents, we seek a deeper understanding of its mode of action. To that end, we employed site-directed mutagenesis of a bacterial cytochrome
b
, combined with biophysical and biochemical measurements. A large scale domain movement involving the iron-sulfur protein subunit is required for electron transfer from cytochrome
b
-bound ubihydroquinone to cytochrome
c
1
of the cytochrome
bc
1
complex. Here, we show that atovaquone blocks this domain movement by locking the iron-sulfur subunit in its cytochrome
b
-binding conformation. Based on our malaria atovaquone resistance data, a series of cytochrome
b
mutants was produced that were predicted to have either enhanced or reduced sensitivity to atovaquone. Mutations altering the bacterial cytochrome
b
at its
ef
loop to more closely resemble
Plasmodium
cytochrome
b
increased the sensitivity of the cytochrome
bc
1
complex to atovaquone, whereas a mutation within the
ef
loop that is associated with resistance in malaria parasites rendered it resistant to atovaquone. Interestingly, the atovaquone resistance-associated mutation led to a 10-fold reduction in the efficiency of the cytochrome
bc
1
complex, suggesting that it may exert a cost on efficiency of the cytochrome
bc
1
complex, without compromising seriously the growth of the organism.
Metrics
Details
- Title
- Uncovering the Molecular Mode of Action of the Antimalarial Drug Atovaquone Using a Bacterial System
- Creators
- Michael W Mather - From the Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 19129 andElisabeth Darrouzet - Department of Biology, Plant Science Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104Maria Valkova-Valchanova - Department of Biology, Plant Science Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104Jason W Cooley - Department of Biology, Plant Science Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104Michael T McIntosh - From the Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 19129 andFevzi Daldal - Department of Biology, Plant Science Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104Akhil B Vaidya - From the Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 19129 and
- Publication Details
- The Journal of biological chemistry, v 280(29), pp 27458-27465
- Publisher
- ASBMB Publications / Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000230589500098
- Scopus ID
- 2-s2.0-22844435982
- Other Identifier
- 991014878214404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology