Dichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis.
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2021 |
| Outros Autores: | , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | por |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| DOI: | 10.1128/mSphere.01002-20 |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/46127 |
Resumo: | 2021 |
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Ferrarini, Mariana GalvãoNisimura, Lindice MitieGirard, Richard Marcel Bruno MoreiraAlencar, Mayke BezerraFragoso, Mariana Sayuri IshikawaAraújo-Silva, Carlla AssisVeiga, Alan de AlmeidaAbud, Ana Paula RessettiNardelli, Sheila CristinaVommaro, Rossiane C.Silber, Ariel MarianoFrance-Sagot, MarieÁvila, Andréa Rodrigues2021-02-22T14:00:51Z2021-02-22T14:00:51Z2021FERRARINI, Mariana Galvão. et al. Dichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis. Msphere, v.6, n. 1, p. 1–20, 2021.2379-5042https://www.arca.fiocruz.br/handle/icict/4612710.1128/mSphere.01002-20porAmerican Society for MicrobiologyDicloroacetato de sódioDCAToxoplasmosisDichloroacetic AcidMetabolismDrug TherapyToxoplasmosisÁcido DicloroacéticoMetabolismoQuimioterapiaToxoplasmoseAcide dichloro-acétiqueMétabolismeTraitement médicamenteuxToxoplasmoseÁcido DicloroacéticoMetabolismoTratamento FarmacológicoDichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis.info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article2021Université de Lyon. Laboratoire de Biometrié et Biologie Evolutive. Lyon, France.Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Pesquisa em Apicomplexa. Curitiba, PR, Brasil.Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Parasitologia. Laboratório de Bioquímica de Trips. São Paulo, SP, Brasil.Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Parasitologia. Laboratório de Bioquímica de Trips. São Paulo, SP, Brasil.Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Pesquisa em Apicomplexa. Curitiba, PR, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Ultraestrutura Celular Hertha Meyer. Rio de Janeiro, RJ, Brasil. / Universidade Federal do Rio de Janeiro. Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Pesquisa em Apicomplexa. Curitiba, PR, Brasil.Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Pesquisa em Apicomplexa. Curitiba, PR, Brasil.Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Pesquisa em Apicomplexa. Curitiba, PR, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Ultraestrutura Celular Hertha Meyer. Rio de Janeiro, RJ, Brasil. / Universidade Federal do Rio de Janeiro. Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens. Rio de Janeiro, RJ, Brasil.Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Parasitologia. Laboratório de Bioquímica de Trips. São Paulo, SP, Brasil.Université de Lyon. Laboratoire de Biometrié et Biologie Evolutive. Lyon, France. / INRIA Grenoble Rhône-Alpes, Montbonnot-Saint-Martin, France.Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Pesquisa em Apicomplexa. Curitiba, PR, Brasil.Toxoplasmosis, a protozoan infection caused by Toxoplasma gondii, is estimated to affect around 2.5 billion people worldwide. Nevertheless, the side effects of drugs combined with the long period of therapy usually result in discontinuation of the treatment. New therapies should be developed by exploring peculiarities of the parasite’s metabolic pathways, similarly to what has been well described in cancer cell metabolism. An example is the switch in the metabolism of cancer that blocks the conversion of pyruvate into acetyl coenzyme A in mitochondria. In this context, dichloroacetate (DCA) is an anticancer drug that reverts the tumor proliferation by inhibiting the enzymes responsible for this switch: the pyruvate dehydrogenase kinases (PDKs). DCA has also been used in the treatment of certain symptoms of malaria; however, there is no evidence of how this drug affects apicomplexan species. In this paper, we studied the metabolism of T. gondii and demonstrate that DCA also inhibits T. gondii’s in vitro infection with no toxic effects on host cells. DCA caused an increase in the activity of pyruvate dehydrogenase followed by an unbalanced mitochondrial activity. We also observed morphological alterations frequently in mitochondria and in a few apicoplasts, essential organelles for parasite survival. To date, the kinases that potentially regulate the activity of pyruvate metabolism in both organelles have never been described. Here, we confirmed the presence in the genome of two putative kinases (T. gondii PDK [TgPDK] and T. gondii branched-chain a-keto acid dehydrogenase kinase [TgBCKDK]), verified their cellular localization in the mitochondrion, and provided in silico data suggesting that they are potential targets of DCA.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-83084https://www.arca.fiocruz.br/bitstream/icict/46127/1/license.txt783568c2893d2e25a99990b126be1772MD51ORIGINALmSphere.01002-20OK.pdfmSphere.01002-20OK.pdfapplication/pdf4092396https://www.arca.fiocruz.br/bitstream/icict/46127/2/mSphere.01002-20OK.pdf9920ff6877b791870cd2ed6945132808MD52TEXTmSphere.01002-20OK.pdf.txtmSphere.01002-20OK.pdf.txtExtracted 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| dc.title.pt_BR.fl_str_mv |
Dichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis. |
| title |
Dichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis. |
| spellingShingle |
Dichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis. Ferrarini, Mariana Galvão Dicloroacetato de sódio DCA Toxoplasmosis Dichloroacetic Acid Metabolism Drug Therapy Toxoplasmosis Ácido Dicloroacético Metabolismo Quimioterapia Toxoplasmose Acide dichloro-acétique Métabolisme Traitement médicamenteux Toxoplasmose Ácido Dicloroacético Metabolismo Tratamento Farmacológico |
| title_short |
Dichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis. |
| title_full |
Dichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis. |
| title_fullStr |
Dichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis. |
| title_full_unstemmed |
Dichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis. |
| title_sort |
Dichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis. |
| author |
Ferrarini, Mariana Galvão |
| author_facet |
Ferrarini, Mariana Galvão Nisimura, Lindice Mitie Girard, Richard Marcel Bruno Moreira Alencar, Mayke Bezerra Fragoso, Mariana Sayuri Ishikawa Araújo-Silva, Carlla Assis Veiga, Alan de Almeida Abud, Ana Paula Ressetti Nardelli, Sheila Cristina Vommaro, Rossiane C. Silber, Ariel Mariano France-Sagot, Marie Ávila, Andréa Rodrigues |
| author_role |
author |
| author2 |
Nisimura, Lindice Mitie Girard, Richard Marcel Bruno Moreira Alencar, Mayke Bezerra Fragoso, Mariana Sayuri Ishikawa Araújo-Silva, Carlla Assis Veiga, Alan de Almeida Abud, Ana Paula Ressetti Nardelli, Sheila Cristina Vommaro, Rossiane C. Silber, Ariel Mariano France-Sagot, Marie Ávila, Andréa Rodrigues |
| author2_role |
author author author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Ferrarini, Mariana Galvão Nisimura, Lindice Mitie Girard, Richard Marcel Bruno Moreira Alencar, Mayke Bezerra Fragoso, Mariana Sayuri Ishikawa Araújo-Silva, Carlla Assis Veiga, Alan de Almeida Abud, Ana Paula Ressetti Nardelli, Sheila Cristina Vommaro, Rossiane C. Silber, Ariel Mariano France-Sagot, Marie Ávila, Andréa Rodrigues |
| dc.subject.other.pt_BR.fl_str_mv |
Dicloroacetato de sódio DCA |
| topic |
Dicloroacetato de sódio DCA Toxoplasmosis Dichloroacetic Acid Metabolism Drug Therapy Toxoplasmosis Ácido Dicloroacético Metabolismo Quimioterapia Toxoplasmose Acide dichloro-acétique Métabolisme Traitement médicamenteux Toxoplasmose Ácido Dicloroacético Metabolismo Tratamento Farmacológico |
| dc.subject.en.pt_BR.fl_str_mv |
Toxoplasmosis Dichloroacetic Acid Metabolism Drug Therapy |
| dc.subject.es.pt_BR.fl_str_mv |
Toxoplasmosis Ácido Dicloroacético Metabolismo Quimioterapia |
| dc.subject.fr.pt_BR.fl_str_mv |
Toxoplasmose Acide dichloro-acétique Métabolisme Traitement médicamenteux |
| dc.subject.decs.pt_BR.fl_str_mv |
Toxoplasmose Ácido Dicloroacético Metabolismo Tratamento Farmacológico |
| description |
2021 |
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2021 |
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2021-02-22T14:00:51Z |
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2021-02-22T14:00:51Z |
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2021 |
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info:eu-repo/semantics/article |
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FERRARINI, Mariana Galvão. et al. Dichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis. Msphere, v.6, n. 1, p. 1–20, 2021. |
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https://www.arca.fiocruz.br/handle/icict/46127 |
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2379-5042 |
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10.1128/mSphere.01002-20 |
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FERRARINI, Mariana Galvão. et al. Dichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis. Msphere, v.6, n. 1, p. 1–20, 2021. 2379-5042 10.1128/mSphere.01002-20 |
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American Society for Microbiology |
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American Society for Microbiology |
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