Genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in Trypanosoma cruzi.
Chagas disease is a neglected tropical disease and a leading cause of heart failure in Latin America caused by a protozoan called Trypanosoma cruzi. This parasite presents a complex multi-stage life cycle. Anti-Chagas drugs currently available are limited to benznidazole and nifurtimox, both with se...
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ftdoajarticles:oai:doaj.org/article:84a796d0ce1148a1bb855932c99ffcc9 2023-05-15T15:10:59+02:00 Genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in Trypanosoma cruzi. Isabel S Shiratsubaki Xin Fang Rodolpho O O Souza Bernhard O Palsson Ariel M Silber Jair L Siqueira-Neto 2020-10-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0008728 https://doaj.org/article/84a796d0ce1148a1bb855932c99ffcc9 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0008728 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0008728 https://doaj.org/article/84a796d0ce1148a1bb855932c99ffcc9 PLoS Neglected Tropical Diseases, Vol 14, Iss 10, p e0008728 (2020) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2020 ftdoajarticles https://doi.org/10.1371/journal.pntd.0008728 2022-12-31T11:55:03Z Chagas disease is a neglected tropical disease and a leading cause of heart failure in Latin America caused by a protozoan called Trypanosoma cruzi. This parasite presents a complex multi-stage life cycle. Anti-Chagas drugs currently available are limited to benznidazole and nifurtimox, both with severe side effects. Thus, there is a need for alternative and more efficient drugs. Genome-scale metabolic models (GEMs) can accurately predict metabolic capabilities and aid in drug discovery in metabolic genes. This work developed an extended GEM, hereafter referred to as iIS312, of the published and validated T. cruzi core metabolism model. From iIS312, we then built three stage-specific models through transcriptomics data integration, and showed that epimastigotes present the most active metabolism among the stages (see S1-S4 GEMs). Stage-specific models predicted significant metabolic differences among stages, including variations in flux distribution in core metabolism. Moreover, the gene essentiality predictions suggest potential drug targets, among which some have been previously proven lethal, including glutamate dehydrogenase, glucokinase and hexokinase. To validate the models, we measured the activity of enzymes in the core metabolism of the parasite at different stages, and showed the results were consistent with model predictions. Our results represent a potential step forward towards the improvement of Chagas disease treatment. To our knowledge, these stage-specific models are the first GEMs built for the stages Amastigote and Trypomastigote. This work is also the first to present an in silico GEM comparison among different stages in the T. cruzi life cycle. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 14 10 e0008728 |
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Directory of Open Access Journals: DOAJ Articles |
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English |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Isabel S Shiratsubaki Xin Fang Rodolpho O O Souza Bernhard O Palsson Ariel M Silber Jair L Siqueira-Neto Genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in Trypanosoma cruzi. |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Chagas disease is a neglected tropical disease and a leading cause of heart failure in Latin America caused by a protozoan called Trypanosoma cruzi. This parasite presents a complex multi-stage life cycle. Anti-Chagas drugs currently available are limited to benznidazole and nifurtimox, both with severe side effects. Thus, there is a need for alternative and more efficient drugs. Genome-scale metabolic models (GEMs) can accurately predict metabolic capabilities and aid in drug discovery in metabolic genes. This work developed an extended GEM, hereafter referred to as iIS312, of the published and validated T. cruzi core metabolism model. From iIS312, we then built three stage-specific models through transcriptomics data integration, and showed that epimastigotes present the most active metabolism among the stages (see S1-S4 GEMs). Stage-specific models predicted significant metabolic differences among stages, including variations in flux distribution in core metabolism. Moreover, the gene essentiality predictions suggest potential drug targets, among which some have been previously proven lethal, including glutamate dehydrogenase, glucokinase and hexokinase. To validate the models, we measured the activity of enzymes in the core metabolism of the parasite at different stages, and showed the results were consistent with model predictions. Our results represent a potential step forward towards the improvement of Chagas disease treatment. To our knowledge, these stage-specific models are the first GEMs built for the stages Amastigote and Trypomastigote. This work is also the first to present an in silico GEM comparison among different stages in the T. cruzi life cycle. |
format |
Article in Journal/Newspaper |
author |
Isabel S Shiratsubaki Xin Fang Rodolpho O O Souza Bernhard O Palsson Ariel M Silber Jair L Siqueira-Neto |
author_facet |
Isabel S Shiratsubaki Xin Fang Rodolpho O O Souza Bernhard O Palsson Ariel M Silber Jair L Siqueira-Neto |
author_sort |
Isabel S Shiratsubaki |
title |
Genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in Trypanosoma cruzi. |
title_short |
Genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in Trypanosoma cruzi. |
title_full |
Genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in Trypanosoma cruzi. |
title_fullStr |
Genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in Trypanosoma cruzi. |
title_full_unstemmed |
Genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in Trypanosoma cruzi. |
title_sort |
genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in trypanosoma cruzi. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2020 |
url |
https://doi.org/10.1371/journal.pntd.0008728 https://doaj.org/article/84a796d0ce1148a1bb855932c99ffcc9 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 14, Iss 10, p e0008728 (2020) |
op_relation |
https://doi.org/10.1371/journal.pntd.0008728 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0008728 https://doaj.org/article/84a796d0ce1148a1bb855932c99ffcc9 |
op_doi |
https://doi.org/10.1371/journal.pntd.0008728 |
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PLOS Neglected Tropical Diseases |
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14 |
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10 |
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e0008728 |
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