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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-05-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC4022464?pdf=render |
| _version_ | 1819260998624739328 |
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| author | Cecilia P Sanchez Chia-Hao Liu Sybille Mayer Astutiati Nurhasanah Marek Cyrklaff Jianbing Mu Michael T Ferdig Wilfred D Stein Michael Lanzer |
| author_facet | Cecilia P Sanchez Chia-Hao Liu Sybille Mayer Astutiati Nurhasanah Marek Cyrklaff Jianbing Mu Michael T Ferdig Wilfred D Stein Michael Lanzer |
| author_sort | Cecilia P Sanchez |
| collection | DOAJ |
| 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 IC50 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. |
| first_indexed | 2024-12-23T19:34:49Z |
| format | Article |
| id | doaj.art-b8a0c684db08460f8f748bb50b61abfb |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-23T19:34:49Z |
| publishDate | 2014-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-b8a0c684db08460f8f748bb50b61abfb2022-12-21T17:33:48ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042014-05-01105e100438210.1371/journal.pgen.1004382A HECT ubiquitin-protein ligase as a novel candidate gene for altered quinine and quinidine responses in Plasmodium falciparum.Cecilia P SanchezChia-Hao LiuSybille MayerAstutiati NurhasanahMarek CyrklaffJianbing MuMichael T FerdigWilfred D SteinMichael LanzerThe 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 IC50 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.http://europepmc.org/articles/PMC4022464?pdf=render |
| spellingShingle | Cecilia P Sanchez Chia-Hao Liu Sybille Mayer Astutiati Nurhasanah Marek Cyrklaff Jianbing Mu Michael T Ferdig Wilfred D Stein Michael Lanzer A HECT ubiquitin-protein ligase as a novel candidate gene for altered quinine and quinidine responses in Plasmodium falciparum. PLoS Genetics |
| title | A HECT ubiquitin-protein ligase as a novel candidate gene for altered quinine and quinidine responses in Plasmodium falciparum. |
| title_full | A HECT ubiquitin-protein ligase as a novel candidate gene for altered quinine and quinidine responses in Plasmodium falciparum. |
| title_fullStr | A HECT ubiquitin-protein ligase as a novel candidate gene for altered quinine and quinidine responses in Plasmodium falciparum. |
| title_full_unstemmed | A HECT ubiquitin-protein ligase as a novel candidate gene for altered quinine and quinidine responses in Plasmodium falciparum. |
| title_short | A HECT ubiquitin-protein ligase as a novel candidate gene for altered quinine and quinidine responses in Plasmodium falciparum. |
| title_sort | hect ubiquitin protein ligase as a novel candidate gene for altered quinine and quinidine responses in plasmodium falciparum |
| url | http://europepmc.org/articles/PMC4022464?pdf=render |
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