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A HECT Ubiquitin-Protein Ligase as a Novel Candidate Gene for Altered Quinine and Quinidine Responses in Plasmodium falciparum
The emerging resistance to quinine jeopardizes the efficacy of a drug that has been used in the treatment of malaria for several centuries. To identify factors contributing to differential quinine responses in the human malaria parasite Plasmodium falciparum, we have conducted comparative quantitati...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022464/ https://www.ncbi.nlm.nih.gov/pubmed/24830312 http://dx.doi.org/10.1371/journal.pgen.1004382 |
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author | Sanchez, Cecilia P. Liu, Chia-Hao Mayer, Sybille Nurhasanah, Astutiati Cyrklaff, Marek Mu, Jianbing Ferdig, Michael T. Stein, Wilfred D. Lanzer, Michael |
author_facet | Sanchez, Cecilia P. Liu, Chia-Hao Mayer, Sybille Nurhasanah, Astutiati Cyrklaff, Marek Mu, Jianbing Ferdig, Michael T. Stein, Wilfred D. Lanzer, Michael |
author_sort | Sanchez, Cecilia P. |
collection | PubMed |
description | The emerging resistance to quinine jeopardizes the efficacy of a drug that has been used in the treatment of malaria for several centuries. To identify factors contributing to differential quinine responses in the human malaria parasite Plasmodium falciparum, we have conducted comparative quantitative trait locus analyses on the susceptibility to quinine and also its stereoisomer quinidine, and on the initial and steady-state intracellular drug accumulation levels in the F1 progeny of a genetic cross. These data, together with genetic screens of field isolates and laboratory strains associated differential quinine and quinidine responses with mutated pfcrt, a segment on chromosome 13, and a novel candidate gene, termed MAL7P1.19 (encoding a HECT ubiquitin ligase). Despite a strong likelihood of association, episomal transfections demonstrated a role for the HECT ubiquitin-protein ligase in quinine and quinidine sensitivity in only a subset of genetic backgrounds, and here the changes in IC(50) values were moderate (approximately 2-fold). These data show that quinine responsiveness is a complex genetic trait with multiple alleles playing a role and that more experiments are needed to unravel the role of the contributing factors. |
format | Online Article Text |
id | pubmed-4022464 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-40224642014-05-21 A HECT Ubiquitin-Protein Ligase as a Novel Candidate Gene for Altered Quinine and Quinidine Responses in Plasmodium falciparum Sanchez, Cecilia P. Liu, Chia-Hao Mayer, Sybille Nurhasanah, Astutiati Cyrklaff, Marek Mu, Jianbing Ferdig, Michael T. Stein, Wilfred D. Lanzer, Michael PLoS Genet Research Article The emerging resistance to quinine jeopardizes the efficacy of a drug that has been used in the treatment of malaria for several centuries. To identify factors contributing to differential quinine responses in the human malaria parasite Plasmodium falciparum, we have conducted comparative quantitative trait locus analyses on the susceptibility to quinine and also its stereoisomer quinidine, and on the initial and steady-state intracellular drug accumulation levels in the F1 progeny of a genetic cross. These data, together with genetic screens of field isolates and laboratory strains associated differential quinine and quinidine responses with mutated pfcrt, a segment on chromosome 13, and a novel candidate gene, termed MAL7P1.19 (encoding a HECT ubiquitin ligase). Despite a strong likelihood of association, episomal transfections demonstrated a role for the HECT ubiquitin-protein ligase in quinine and quinidine sensitivity in only a subset of genetic backgrounds, and here the changes in IC(50) values were moderate (approximately 2-fold). These data show that quinine responsiveness is a complex genetic trait with multiple alleles playing a role and that more experiments are needed to unravel the role of the contributing factors. Public Library of Science 2014-05-15 /pmc/articles/PMC4022464/ /pubmed/24830312 http://dx.doi.org/10.1371/journal.pgen.1004382 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article Sanchez, Cecilia P. Liu, Chia-Hao Mayer, Sybille Nurhasanah, Astutiati Cyrklaff, Marek Mu, Jianbing Ferdig, Michael T. Stein, Wilfred D. Lanzer, Michael A HECT Ubiquitin-Protein Ligase as a Novel Candidate Gene for Altered Quinine and Quinidine Responses in Plasmodium falciparum |
title | A HECT Ubiquitin-Protein Ligase as a Novel Candidate Gene for Altered Quinine and Quinidine Responses in Plasmodium falciparum
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title_full | A HECT Ubiquitin-Protein Ligase as a Novel Candidate Gene for Altered Quinine and Quinidine Responses in Plasmodium falciparum
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title_fullStr | A HECT Ubiquitin-Protein Ligase as a Novel Candidate Gene for Altered Quinine and Quinidine Responses in Plasmodium falciparum
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title_full_unstemmed | A HECT Ubiquitin-Protein Ligase as a Novel Candidate Gene for Altered Quinine and Quinidine Responses in Plasmodium falciparum
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title_short | A HECT Ubiquitin-Protein Ligase as a Novel Candidate Gene for Altered Quinine and Quinidine Responses in Plasmodium falciparum
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title_sort | hect ubiquitin-protein ligase as a novel candidate gene for altered quinine and quinidine responses in plasmodium falciparum |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022464/ https://www.ncbi.nlm.nih.gov/pubmed/24830312 http://dx.doi.org/10.1371/journal.pgen.1004382 |
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