Author | Ferrarini, Mariana Galvão | |
Author | Nisimura, Lindice Mitie | |
Author | Girard, Richard Marcel Bruno Moreira | |
Author | Alencar, Mayke Bezerra | |
Author | Fragoso, Mariana Sayuri Ishikawa | |
Author | Araújo-Silva, Carlla Assis | |
Author | Veiga, Alan de Almeida | |
Author | Abud, Ana Paula Ressetti | |
Author | Nardelli, Sheila Cristina | |
Author | Vommaro, Rossiane C. | |
Author | Silber, Ariel Mariano | |
Author | France-Sagot, Marie | |
Author | Ávila, Andréa Rodrigues | |
Access date | 2021-02-22T14:00:51Z | |
Available date | 2021-02-22T14:00:51Z | |
Document date | 2021 | |
Citation | 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. | pt_BR |
ISSN | 2379-5042 | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/46127 | |
Language | por | pt_BR |
Publisher | American Society for Microbiology | pt_BR |
Rights | open access | pt_BR |
Subject in Portuguese | Dicloroacetato de sódio | pt_BR |
Subject in Portuguese | DCA | pt_BR |
Title | Dichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis. | pt_BR |
Type | Article | pt_BR |
DOI | 10.1128/mSphere.01002-20 | |
Abstract | 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. | pt_BR |
Affilliation | Université de Lyon. Laboratoire de Biometrié et Biologie Evolutive. Lyon, France. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Pesquisa em Apicomplexa. Curitiba, PR, Brasil. | pt_BR |
Affilliation | Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Parasitologia. Laboratório de Bioquímica de Trips. São Paulo, SP, Brasil. | pt_BR |
Affilliation | Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Parasitologia. Laboratório de Bioquímica de Trips. São Paulo, SP, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Pesquisa em Apicomplexa. Curitiba, PR, Brasil. | pt_BR |
Affilliation | 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. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Pesquisa em Apicomplexa. Curitiba, PR, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Pesquisa em Apicomplexa. Curitiba, PR, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Pesquisa em Apicomplexa. Curitiba, PR, Brasil. | pt_BR |
Affilliation | 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. | pt_BR |
Affilliation | Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Parasitologia. Laboratório de Bioquímica de Trips. São Paulo, SP, Brasil. | pt_BR |
Affilliation | Université de Lyon. Laboratoire de Biometrié et Biologie Evolutive. Lyon, France. / INRIA Grenoble Rhône-Alpes, Montbonnot-Saint-Martin, France. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Pesquisa em Apicomplexa. Curitiba, PR, Brasil. | pt_BR |
Subject | Toxoplasmosis | pt_BR |
Subject | Dichloroacetic Acid | pt_BR |
Subject | Metabolism | pt_BR |
Subject | Drug Therapy | pt_BR |
Subject in Spanish | Toxoplasmosis | pt_BR |
Subject in Spanish | Ácido Dicloroacético | pt_BR |
Subject in Spanish | Metabolismo | pt_BR |
Subject in Spanish | Quimioterapia | pt_BR |
Subject in French | Toxoplasmose | pt_BR |
Subject in French | Acide dichloro-acétique | pt_BR |
Subject in French | Métabolisme | pt_BR |
Subject in French | Traitement médicamenteux | pt_BR |
DeCS | Toxoplasmose | pt_BR |
DeCS | Ácido Dicloroacético | pt_BR |
DeCS | Metabolismo | pt_BR |
DeCS | Tratamento Farmacológico | pt_BR |
Embargo date | 2021 | |