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Biochemical studies of membrane bound Plasmodium falciparum mitochondrial L-malate:quinone oxidoreductase, a potential drug target.
- Source :
-
Biochimica et biophysica acta. Bioenergetics [Biochim Biophys Acta Bioenerg] 2018 Mar; Vol. 1859 (3), pp. 191-200. Date of Electronic Publication: 2017 Dec 18. - Publication Year :
- 2018
-
Abstract
- Plasmodium falciparum is an apicomplexan parasite that causes the most severe malaria in humans. Due to a lack of effective vaccines and emerging of drug resistance parasites, development of drugs with novel mechanisms of action and few side effects are imperative. To this end, ideal drug targets are those essential to parasite viability as well as absent in their mammalian hosts. The mitochondrial electron transport chain (ETC) of P. falciparum is one source of such potential targets because enzymes, such as L-malate:quinone oxidoreductase (PfMQO), in this pathway are absent humans. PfMQO catalyzes the oxidation of L-malate to oxaloacetate and the simultaneous reduction of ubiquinone to ubiquinol. It is a membrane protein, involved in three pathways (ETC, the tricarboxylic acid cycle and the fumarate cycle) and has been shown to be essential for parasite survival, at least, in the intra-erythrocytic asexual stage. These findings indicate that PfMQO would be a valuable drug target for development of antimalarial with novel mechanism of action. Up to this point in time, difficulty in producing active recombinant mitochondrial MQO has hampered biochemical characterization and targeted drug discovery with MQO. Here we report for the first time recombinant PfMQO overexpressed in bacterial membrane and the first biochemical study. Furthermore, about 113 compounds, consisting of ubiquinone binding site inhibitors and antiparasitic agents, were screened resulting in the discovery of ferulenol as a potent PfMQO inhibitor. Finally, ferulenol was shown to inhibit parasite growth and showed strong synergism in combination with atovaquone, a well-described anti-malarial and bc <subscript>1</subscript> complex inhibitor.<br /> (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Subjects :
- Antimalarials pharmacology
Atovaquone pharmacology
Biocatalysis drug effects
Coumarins pharmacology
Drug Synergism
Enzyme Inhibitors pharmacology
Humans
Malaria, Falciparum parasitology
Malaria, Falciparum prevention & control
Malates metabolism
Mitochondrial Membranes drug effects
Oxaloacetic Acid metabolism
Oxidoreductases antagonists & inhibitors
Plasmodium falciparum drug effects
Protozoan Proteins antagonists & inhibitors
Mitochondrial Membranes enzymology
Oxidoreductases metabolism
Plasmodium falciparum enzymology
Protozoan Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0005-2728
- Volume :
- 1859
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta. Bioenergetics
- Publication Type :
- Academic Journal
- Accession number :
- 29269266
- Full Text :
- https://doi.org/10.1016/j.bbabio.2017.12.004