Perturbation of the dimer interface of triosephosphate isomerase and its effect on Trypanosoma cruzi.

<h4>Background</h4>Chagas disease affects around 18 million people in the American continent. Unfortunately, there is no satisfactory treatment for the disease. The drugs currently used are not specific and exert serious toxic effects. Thus, there is an urgent need for drugs that are eff...

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Autores principales:	Vanesa Olivares-Illana, Adela Rodríguez-Romero, Ingeborg Becker, Miriam Berzunza, Juventino García, Ruy Pérez-Montfort, Nallely Cabrera, Francisco López-Calahorra, Marieta Tuena de Gómez-Puyou, Armando Gómez-Puyou
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2007
Materias:	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/2aeb4e994377455d9215a7851a76ceff
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spelling	oai:doaj.org-article:2aeb4e994377455d9215a7851a76ceff2021-11-25T06:32:27ZPerturbation of the dimer interface of triosephosphate isomerase and its effect on Trypanosoma cruzi.1935-27271935-273510.1371/journal.pntd.0000001https://doaj.org/article/2aeb4e994377455d9215a7851a76ceff2007-10-01T00:00:00Zhttps://doi.org/10.1371/journal.pntd.0000001https://doaj.org/toc/1935-2727https://doaj.org/toc/1935-2735<h4>Background</h4>Chagas disease affects around 18 million people in the American continent. Unfortunately, there is no satisfactory treatment for the disease. The drugs currently used are not specific and exert serious toxic effects. Thus, there is an urgent need for drugs that are effective. Looking for molecules to eliminate the parasite, we have targeted a central enzyme of the glycolytic pathway: triosephosphate isomerase (TIM). The homodimeric enzyme is catalytically active only as a dimer. Because there are significant differences in the interface of the enzymes from the parasite and humans, we searched for small molecules that specifically disrupt contact between the two subunits of the enzyme from Trypanosoma cruzi but not those of TIM from Homo sapiens (HTIM), and tested if they kill the parasite.<h4>Methodology/principal findings</h4>Dithiodianiline (DTDA) at nanomolar concentrations completely inactivates recombinant TIM of T. cruzi (TcTIM). It also inactivated HTIM, but at concentrations around 400 times higher. DTDA was also tested on four TcTIM mutants with each of its four cysteines replaced with either valine or alanine. The sensitivity of the mutants to DTDA was markedly similar to that of the wild type. The crystal structure of the TcTIM soaked in DTDA at 2.15 A resolution, and the data on the mutants showed that inactivation resulted from alterations of the dimer interface. DTDA also prevented the growth of Escherichia coli cells transformed with TcTIM, had no effect on normal E. coli, and also killed T. cruzi epimastigotes in culture.<h4>Conclusions/significance</h4>By targeting on the dimer interface of oligomeric enzymes from parasites, it is possible to discover small molecules that selectively thwart the life of the parasite. Also, the conformational changes that DTDA induces in the dimer interface of the trypanosomal enzyme are unique and identify a region of the interface that could be targeted for drug discovery.Vanesa Olivares-IllanaAdela Rodríguez-RomeroIngeborg BeckerMiriam BerzunzaJuventino GarcíaRuy Pérez-MontfortNallely CabreraFrancisco López-CalahorraMarieta Tuena de Gómez-PuyouArmando Gómez-PuyouPublic Library of Science (PLoS)articleArctic medicine. Tropical medicineRC955-962Public aspects of medicineRA1-1270ENPLoS Neglected Tropical Diseases, Vol 1, Iss 1, p e1 (2007)
institution	DOAJ
collection	DOAJ
language	EN
topic	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
spellingShingle	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Vanesa Olivares-Illana Adela Rodríguez-Romero Ingeborg Becker Miriam Berzunza Juventino García Ruy Pérez-Montfort Nallely Cabrera Francisco López-Calahorra Marieta Tuena de Gómez-Puyou Armando Gómez-Puyou Perturbation of the dimer interface of triosephosphate isomerase and its effect on Trypanosoma cruzi.
description	<h4>Background</h4>Chagas disease affects around 18 million people in the American continent. Unfortunately, there is no satisfactory treatment for the disease. The drugs currently used are not specific and exert serious toxic effects. Thus, there is an urgent need for drugs that are effective. Looking for molecules to eliminate the parasite, we have targeted a central enzyme of the glycolytic pathway: triosephosphate isomerase (TIM). The homodimeric enzyme is catalytically active only as a dimer. Because there are significant differences in the interface of the enzymes from the parasite and humans, we searched for small molecules that specifically disrupt contact between the two subunits of the enzyme from Trypanosoma cruzi but not those of TIM from Homo sapiens (HTIM), and tested if they kill the parasite.<h4>Methodology/principal findings</h4>Dithiodianiline (DTDA) at nanomolar concentrations completely inactivates recombinant TIM of T. cruzi (TcTIM). It also inactivated HTIM, but at concentrations around 400 times higher. DTDA was also tested on four TcTIM mutants with each of its four cysteines replaced with either valine or alanine. The sensitivity of the mutants to DTDA was markedly similar to that of the wild type. The crystal structure of the TcTIM soaked in DTDA at 2.15 A resolution, and the data on the mutants showed that inactivation resulted from alterations of the dimer interface. DTDA also prevented the growth of Escherichia coli cells transformed with TcTIM, had no effect on normal E. coli, and also killed T. cruzi epimastigotes in culture.<h4>Conclusions/significance</h4>By targeting on the dimer interface of oligomeric enzymes from parasites, it is possible to discover small molecules that selectively thwart the life of the parasite. Also, the conformational changes that DTDA induces in the dimer interface of the trypanosomal enzyme are unique and identify a region of the interface that could be targeted for drug discovery.
format	article
author	Vanesa Olivares-Illana Adela Rodríguez-Romero Ingeborg Becker Miriam Berzunza Juventino García Ruy Pérez-Montfort Nallely Cabrera Francisco López-Calahorra Marieta Tuena de Gómez-Puyou Armando Gómez-Puyou
author_facet	Vanesa Olivares-Illana Adela Rodríguez-Romero Ingeborg Becker Miriam Berzunza Juventino García Ruy Pérez-Montfort Nallely Cabrera Francisco López-Calahorra Marieta Tuena de Gómez-Puyou Armando Gómez-Puyou
author_sort	Vanesa Olivares-Illana
title	Perturbation of the dimer interface of triosephosphate isomerase and its effect on Trypanosoma cruzi.
title_short	Perturbation of the dimer interface of triosephosphate isomerase and its effect on Trypanosoma cruzi.
title_full	Perturbation of the dimer interface of triosephosphate isomerase and its effect on Trypanosoma cruzi.
title_fullStr	Perturbation of the dimer interface of triosephosphate isomerase and its effect on Trypanosoma cruzi.
title_full_unstemmed	Perturbation of the dimer interface of triosephosphate isomerase and its effect on Trypanosoma cruzi.
title_sort	perturbation of the dimer interface of triosephosphate isomerase and its effect on trypanosoma cruzi.
publisher	Public Library of Science (PLoS)
publishDate	2007
url	https://doaj.org/article/2aeb4e994377455d9215a7851a76ceff
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Perturbation of the dimer interface of triosephosphate isomerase and its effect on Trypanosoma cruzi.

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