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Discovering Thiamine Transporters as Targets of Chloroquine Using a Novel Functional Genomics Strategy
Chloroquine (CQ) and other quinoline-containing antimalarials are important drugs with many therapeutic benefits as well as adverse effects. However, the molecular targets underlying most such effects are largely unknown. By taking a novel functional genomics strategy, which employs a unique combina...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510038/ https://www.ncbi.nlm.nih.gov/pubmed/23209439 http://dx.doi.org/10.1371/journal.pgen.1003083 |
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author | Huang, Zhiwei Srinivasan, Sankaranarayanan Zhang, Jianhuai Chen, Kaifu Li, Yongxiang Li, Wei Quiocho, Florante A. Pan, Xuewen |
author_facet | Huang, Zhiwei Srinivasan, Sankaranarayanan Zhang, Jianhuai Chen, Kaifu Li, Yongxiang Li, Wei Quiocho, Florante A. Pan, Xuewen |
author_sort | Huang, Zhiwei |
collection | PubMed |
description | Chloroquine (CQ) and other quinoline-containing antimalarials are important drugs with many therapeutic benefits as well as adverse effects. However, the molecular targets underlying most such effects are largely unknown. By taking a novel functional genomics strategy, which employs a unique combination of genome-wide drug-gene synthetic lethality (DGSL), gene-gene synthetic lethality (GGSL), and dosage suppression (DS) screens in the model organism Saccharomyces cerevisiae and is thus termed SL/DS for simplicity, we found that CQ inhibits the thiamine transporters Thi7, Nrt1, and Thi72 in yeast. We first discovered a thi3Δ mutant as hypersensitive to CQ using a genome-wide DGSL analysis. Using genome-wide GGSL and DS screens, we then found that a thi7Δ mutation confers severe growth defect in the thi3Δ mutant and that THI7 overexpression suppresses CQ-hypersensitivity of this mutant. We subsequently showed that CQ inhibits the functions of Thi7 and its homologues Nrt1 and Thi72. In particular, the transporter activity of wild-type Thi7 but not a CQ-resistant mutant (Thi7(T287N)) was completely inhibited by the drug. Similar effects were also observed with other quinoline-containing antimalarials. In addition, CQ completely inhibited a human thiamine transporter (SLC19A3) expressed in yeast and significantly inhibited thiamine uptake in cultured human cell lines. Therefore, inhibition of thiamine uptake is a conserved mechanism of action of CQ. This study also demonstrated SL/DS as a uniquely effective methodology for discovering drug targets. |
format | Online Article Text |
id | pubmed-3510038 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-35100382012-12-03 Discovering Thiamine Transporters as Targets of Chloroquine Using a Novel Functional Genomics Strategy Huang, Zhiwei Srinivasan, Sankaranarayanan Zhang, Jianhuai Chen, Kaifu Li, Yongxiang Li, Wei Quiocho, Florante A. Pan, Xuewen PLoS Genet Research Article Chloroquine (CQ) and other quinoline-containing antimalarials are important drugs with many therapeutic benefits as well as adverse effects. However, the molecular targets underlying most such effects are largely unknown. By taking a novel functional genomics strategy, which employs a unique combination of genome-wide drug-gene synthetic lethality (DGSL), gene-gene synthetic lethality (GGSL), and dosage suppression (DS) screens in the model organism Saccharomyces cerevisiae and is thus termed SL/DS for simplicity, we found that CQ inhibits the thiamine transporters Thi7, Nrt1, and Thi72 in yeast. We first discovered a thi3Δ mutant as hypersensitive to CQ using a genome-wide DGSL analysis. Using genome-wide GGSL and DS screens, we then found that a thi7Δ mutation confers severe growth defect in the thi3Δ mutant and that THI7 overexpression suppresses CQ-hypersensitivity of this mutant. We subsequently showed that CQ inhibits the functions of Thi7 and its homologues Nrt1 and Thi72. In particular, the transporter activity of wild-type Thi7 but not a CQ-resistant mutant (Thi7(T287N)) was completely inhibited by the drug. Similar effects were also observed with other quinoline-containing antimalarials. In addition, CQ completely inhibited a human thiamine transporter (SLC19A3) expressed in yeast and significantly inhibited thiamine uptake in cultured human cell lines. Therefore, inhibition of thiamine uptake is a conserved mechanism of action of CQ. This study also demonstrated SL/DS as a uniquely effective methodology for discovering drug targets. Public Library of Science 2012-11-29 /pmc/articles/PMC3510038/ /pubmed/23209439 http://dx.doi.org/10.1371/journal.pgen.1003083 Text en © 2012 Huang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Huang, Zhiwei Srinivasan, Sankaranarayanan Zhang, Jianhuai Chen, Kaifu Li, Yongxiang Li, Wei Quiocho, Florante A. Pan, Xuewen Discovering Thiamine Transporters as Targets of Chloroquine Using a Novel Functional Genomics Strategy |
title | Discovering Thiamine Transporters as Targets of Chloroquine Using a Novel Functional Genomics Strategy |
title_full | Discovering Thiamine Transporters as Targets of Chloroquine Using a Novel Functional Genomics Strategy |
title_fullStr | Discovering Thiamine Transporters as Targets of Chloroquine Using a Novel Functional Genomics Strategy |
title_full_unstemmed | Discovering Thiamine Transporters as Targets of Chloroquine Using a Novel Functional Genomics Strategy |
title_short | Discovering Thiamine Transporters as Targets of Chloroquine Using a Novel Functional Genomics Strategy |
title_sort | discovering thiamine transporters as targets of chloroquine using a novel functional genomics strategy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510038/ https://www.ncbi.nlm.nih.gov/pubmed/23209439 http://dx.doi.org/10.1371/journal.pgen.1003083 |
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