Cargando…
On the Mechanism of Chloroquine Resistance in Plasmodium falciparum
Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a ca...
Autores principales: | , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2010
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988812/ https://www.ncbi.nlm.nih.gov/pubmed/21124966 http://dx.doi.org/10.1371/journal.pone.0014064 |
_version_ | 1782192287626821632 |
---|---|
author | Chinappi, Mauro Via, Allegra Marcatili, Paolo Tramontano, Anna |
author_facet | Chinappi, Mauro Via, Allegra Marcatili, Paolo Tramontano, Anna |
author_sort | Chinappi, Mauro |
collection | PubMed |
description | Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data. |
format | Text |
id | pubmed-2988812 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-29888122010-12-01 On the Mechanism of Chloroquine Resistance in Plasmodium falciparum Chinappi, Mauro Via, Allegra Marcatili, Paolo Tramontano, Anna PLoS One Research Article Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data. Public Library of Science 2010-11-19 /pmc/articles/PMC2988812/ /pubmed/21124966 http://dx.doi.org/10.1371/journal.pone.0014064 Text en Chinappi 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 Chinappi, Mauro Via, Allegra Marcatili, Paolo Tramontano, Anna On the Mechanism of Chloroquine Resistance in Plasmodium falciparum |
title | On the Mechanism of Chloroquine Resistance in Plasmodium falciparum
|
title_full | On the Mechanism of Chloroquine Resistance in Plasmodium falciparum
|
title_fullStr | On the Mechanism of Chloroquine Resistance in Plasmodium falciparum
|
title_full_unstemmed | On the Mechanism of Chloroquine Resistance in Plasmodium falciparum
|
title_short | On the Mechanism of Chloroquine Resistance in Plasmodium falciparum
|
title_sort | on the mechanism of chloroquine resistance in plasmodium falciparum |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988812/ https://www.ncbi.nlm.nih.gov/pubmed/21124966 http://dx.doi.org/10.1371/journal.pone.0014064 |
work_keys_str_mv | AT chinappimauro onthemechanismofchloroquineresistanceinplasmodiumfalciparum AT viaallegra onthemechanismofchloroquineresistanceinplasmodiumfalciparum AT marcatilipaolo onthemechanismofchloroquineresistanceinplasmodiumfalciparum AT tramontanoanna onthemechanismofchloroquineresistanceinplasmodiumfalciparum |