Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/46127
Title: Dichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis.
Authors: 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
Affilliation: Université 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.
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.
Keywords: Toxoplasmosis
Dichloroacetic Acid
Metabolism
Drug Therapy
???metadata.dc.subject.fr???: Toxoplasmose
Acide dichloro-acétique
Métabolisme
Traitement médicamenteux
Keywords in spanish: Toxoplasmosis
Ácido Dicloroacético
Metabolismo
Quimioterapia
keywords: Dicloroacetato de sódio
DCA
DeCS: Toxoplasmose
Ácido Dicloroacético
Metabolismo
Tratamento Farmacológico
Issue Date: 2021
Publisher: American Society for Microbiology
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.
DOI: 10.1128/mSphere.01002-20
ISSN: 2379-5042
Embargo date: 2021
Copyright: open access
Appears in Collections:PR - ICC - Artigos de Periódicos
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