Dichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis.

dc.creatorFerrarini, Mariana Galvão
dc.creatorNisimura, Lindice Mitie
dc.creatorGirard, Richard Marcel Bruno Moreira
dc.creatorAlencar, Mayke Bezerra
dc.creatorFragoso, Mariana Sayuri Ishikawa
dc.creatorAraújo-Silva, Carlla Assis
dc.creatorVeiga, Alan de Almeida
dc.creatorAbud, Ana Paula Ressetti
dc.creatorNardelli, Sheila Cristina
dc.creatorVommaro, Rossiane C.
dc.creatorSilber, Ariel Mariano
dc.creatorFrance-Sagot, Marie
dc.creatorÁvila, Andréa Rodrigues
dc.date2021-02-22T14:00:51Z
dc.date2021-02-22T14:00:51Z
dc.date2021
dc.date.accessioned2023-09-26T23:56:04Z
dc.date.available2023-09-26T23:56:04Z
dc.identifierFERRARINI, 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.
dc.identifier2379-5042
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/46127
dc.identifier10.1128/mSphere.01002-20
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8895748
dc.descriptionToxoplasmosis, 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.
dc.description2021
dc.formatapplication/pdf
dc.languagepor
dc.publisherAmerican Society for Microbiology
dc.rightsopen access
dc.subjectDicloroacetato de sódio
dc.subjectDCA
dc.subjectToxoplasmosis
dc.subjectDichloroacetic Acid
dc.subjectMetabolism
dc.subjectDrug Therapy
dc.subjectToxoplasmosis
dc.subjectÁcido Dicloroacético
dc.subjectMetabolismo
dc.subjectQuimioterapia
dc.subjectToxoplasmose
dc.subjectAcide dichloro-acétique
dc.subjectMétabolisme
dc.subjectTraitement médicamenteux
dc.subjectToxoplasmose
dc.subjectÁcido Dicloroacético
dc.subjectMetabolismo
dc.subjectTratamento Farmacológico
dc.titleDichloroacetate and pyruvate metabolism: pyruvate dehydrogenase kinases as targets worth investigating for effective therapy of toxoplasmosis.
dc.typeArticle


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