Reconstructing the Qo site of Plasmodium falciparum bc 1 complex in the yeast enzyme.

The bc 1 complex of the mitochondrial respiratory chain is essential for Plasmodium falciparum proliferation, the causative agent of human malaria. Therefore, this enzyme is an attractive target for antimalarials. However, biochemical investigations of the parasite enzyme needed for the study of new...

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Autores principales:	Cindy Vallières, Nicholas Fisher, Brigitte Meunier
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fafd6b83f197459db6ee793811726277
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spelling	oai:doaj.org-article:fafd6b83f197459db6ee7938117262772021-11-18T09:00:06ZReconstructing the Qo site of Plasmodium falciparum bc 1 complex in the yeast enzyme.1932-620310.1371/journal.pone.0071726https://doaj.org/article/fafd6b83f197459db6ee7938117262772013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23951230/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The bc 1 complex of the mitochondrial respiratory chain is essential for Plasmodium falciparum proliferation, the causative agent of human malaria. Therefore, this enzyme is an attractive target for antimalarials. However, biochemical investigations of the parasite enzyme needed for the study of new drugs are challenging. In order to facilitate the study of new compounds targeting the enzyme, we are modifying the inhibitor binding sites of the yeast Saccharomyces cerevisiae to generate a complex that mimics the P. falciparum enzyme. In this study we focused on its Qo pocket, the site of atovaquone binding which is a leading antimalarial drug used in treatment and causal prophylaxis. We constructed and studied a series of mutants with modified Qo sites where yeast residues have been replaced by P. falciparum equivalents, or, for comparison, by human equivalents. Mitochondria were prepared from the yeast Plasmodium-like and human-like Qo mutants. We measured the bc 1 complex sensitivity to atovaquone, azoxystrobin, a Qo site targeting fungicide active against P. falciparum and RCQ06, a quinolone-derivative inhibitor of P. falciparum bc 1 complex.The data obtained highlighted variations in the Qo site that could explain the differences in inhibitor sensitivity between yeast, plasmodial and human enzymes. We showed that the yeast Plasmodium-like Qo mutants could be useful and easy-to-use tools for the study of that class of antimalarials.Cindy VallièresNicholas FisherBrigitte MeunierPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 8, p e71726 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cindy Vallières Nicholas Fisher Brigitte Meunier Reconstructing the Qo site of Plasmodium falciparum bc 1 complex in the yeast enzyme.
description	The bc 1 complex of the mitochondrial respiratory chain is essential for Plasmodium falciparum proliferation, the causative agent of human malaria. Therefore, this enzyme is an attractive target for antimalarials. However, biochemical investigations of the parasite enzyme needed for the study of new drugs are challenging. In order to facilitate the study of new compounds targeting the enzyme, we are modifying the inhibitor binding sites of the yeast Saccharomyces cerevisiae to generate a complex that mimics the P. falciparum enzyme. In this study we focused on its Qo pocket, the site of atovaquone binding which is a leading antimalarial drug used in treatment and causal prophylaxis. We constructed and studied a series of mutants with modified Qo sites where yeast residues have been replaced by P. falciparum equivalents, or, for comparison, by human equivalents. Mitochondria were prepared from the yeast Plasmodium-like and human-like Qo mutants. We measured the bc 1 complex sensitivity to atovaquone, azoxystrobin, a Qo site targeting fungicide active against P. falciparum and RCQ06, a quinolone-derivative inhibitor of P. falciparum bc 1 complex.The data obtained highlighted variations in the Qo site that could explain the differences in inhibitor sensitivity between yeast, plasmodial and human enzymes. We showed that the yeast Plasmodium-like Qo mutants could be useful and easy-to-use tools for the study of that class of antimalarials.
format	article
author	Cindy Vallières Nicholas Fisher Brigitte Meunier
author_facet	Cindy Vallières Nicholas Fisher Brigitte Meunier
author_sort	Cindy Vallières
title	Reconstructing the Qo site of Plasmodium falciparum bc 1 complex in the yeast enzyme.
title_short	Reconstructing the Qo site of Plasmodium falciparum bc 1 complex in the yeast enzyme.
title_full	Reconstructing the Qo site of Plasmodium falciparum bc 1 complex in the yeast enzyme.
title_fullStr	Reconstructing the Qo site of Plasmodium falciparum bc 1 complex in the yeast enzyme.
title_full_unstemmed	Reconstructing the Qo site of Plasmodium falciparum bc 1 complex in the yeast enzyme.
title_sort	reconstructing the qo site of plasmodium falciparum bc 1 complex in the yeast enzyme.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/fafd6b83f197459db6ee793811726277
work_keys_str_mv	AT cindyvallieres reconstructingtheqositeofplasmodiumfalciparumbc1complexintheyeastenzyme AT nicholasfisher reconstructingtheqositeofplasmodiumfalciparumbc1complexintheyeastenzyme AT brigittemeunier reconstructingtheqositeofplasmodiumfalciparumbc1complexintheyeastenzyme
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Reconstructing the Qo site of Plasmodium falciparum bc 1 complex in the yeast enzyme.

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