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Plasmodium falciparum Choline Kinase Inhibition Leads to a Major Decrease in Phosphatidylethanolamine Causing Parasite Death
Malaria is a life-threatening disease caused by different species of the protozoan parasite Plasmodium, with P. falciparum being the deadliest. Increasing parasitic resistance to existing antimalarials makes the necessity of novel avenues to treat this disease an urgent priority. The enzymes respons...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018819/ https://www.ncbi.nlm.nih.gov/pubmed/27616047 http://dx.doi.org/10.1038/srep33189 |
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author | Serrán-Aguilera, Lucía Denton, Helen Rubio-Ruiz, Belén López-Gutiérrez, Borja Entrena, Antonio Izquierdo, Luis Smith, Terry K. Conejo-García, Ana Hurtado-Guerrero, Ramon |
author_facet | Serrán-Aguilera, Lucía Denton, Helen Rubio-Ruiz, Belén López-Gutiérrez, Borja Entrena, Antonio Izquierdo, Luis Smith, Terry K. Conejo-García, Ana Hurtado-Guerrero, Ramon |
author_sort | Serrán-Aguilera, Lucía |
collection | PubMed |
description | Malaria is a life-threatening disease caused by different species of the protozoan parasite Plasmodium, with P. falciparum being the deadliest. Increasing parasitic resistance to existing antimalarials makes the necessity of novel avenues to treat this disease an urgent priority. The enzymes responsible for the synthesis of phosphatidylcholine and phosphatidylethanolamine are attractive drug targets to treat malaria as their selective inhibition leads to an arrest of the parasite’s growth and cures malaria in a mouse model. We present here a detailed study that reveals a mode of action for two P. falciparum choline kinase inhibitors both in vitro and in vivo. The compounds present distinct binding modes to the choline/ethanolamine-binding site of P. falciparum choline kinase, reflecting different types of inhibition. Strikingly, these compounds primarily inhibit the ethanolamine kinase activity of the P. falciparum choline kinase, leading to a severe decrease in the phosphatidylethanolamine levels within P. falciparum, which explains the resulting growth phenotype and the parasites death. These studies provide an understanding of the mode of action, and act as a springboard for continued antimalarial development efforts selectively targeting P. falciparum choline kinase. |
format | Online Article Text |
id | pubmed-5018819 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50188192016-09-19 Plasmodium falciparum Choline Kinase Inhibition Leads to a Major Decrease in Phosphatidylethanolamine Causing Parasite Death Serrán-Aguilera, Lucía Denton, Helen Rubio-Ruiz, Belén López-Gutiérrez, Borja Entrena, Antonio Izquierdo, Luis Smith, Terry K. Conejo-García, Ana Hurtado-Guerrero, Ramon Sci Rep Article Malaria is a life-threatening disease caused by different species of the protozoan parasite Plasmodium, with P. falciparum being the deadliest. Increasing parasitic resistance to existing antimalarials makes the necessity of novel avenues to treat this disease an urgent priority. The enzymes responsible for the synthesis of phosphatidylcholine and phosphatidylethanolamine are attractive drug targets to treat malaria as their selective inhibition leads to an arrest of the parasite’s growth and cures malaria in a mouse model. We present here a detailed study that reveals a mode of action for two P. falciparum choline kinase inhibitors both in vitro and in vivo. The compounds present distinct binding modes to the choline/ethanolamine-binding site of P. falciparum choline kinase, reflecting different types of inhibition. Strikingly, these compounds primarily inhibit the ethanolamine kinase activity of the P. falciparum choline kinase, leading to a severe decrease in the phosphatidylethanolamine levels within P. falciparum, which explains the resulting growth phenotype and the parasites death. These studies provide an understanding of the mode of action, and act as a springboard for continued antimalarial development efforts selectively targeting P. falciparum choline kinase. Nature Publishing Group 2016-09-12 /pmc/articles/PMC5018819/ /pubmed/27616047 http://dx.doi.org/10.1038/srep33189 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Serrán-Aguilera, Lucía Denton, Helen Rubio-Ruiz, Belén López-Gutiérrez, Borja Entrena, Antonio Izquierdo, Luis Smith, Terry K. Conejo-García, Ana Hurtado-Guerrero, Ramon Plasmodium falciparum Choline Kinase Inhibition Leads to a Major Decrease in Phosphatidylethanolamine Causing Parasite Death |
title | Plasmodium falciparum Choline Kinase Inhibition Leads to a Major Decrease in Phosphatidylethanolamine Causing Parasite Death |
title_full | Plasmodium falciparum Choline Kinase Inhibition Leads to a Major Decrease in Phosphatidylethanolamine Causing Parasite Death |
title_fullStr | Plasmodium falciparum Choline Kinase Inhibition Leads to a Major Decrease in Phosphatidylethanolamine Causing Parasite Death |
title_full_unstemmed | Plasmodium falciparum Choline Kinase Inhibition Leads to a Major Decrease in Phosphatidylethanolamine Causing Parasite Death |
title_short | Plasmodium falciparum Choline Kinase Inhibition Leads to a Major Decrease in Phosphatidylethanolamine Causing Parasite Death |
title_sort | plasmodium falciparum choline kinase inhibition leads to a major decrease in phosphatidylethanolamine causing parasite death |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018819/ https://www.ncbi.nlm.nih.gov/pubmed/27616047 http://dx.doi.org/10.1038/srep33189 |
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