3-Bromopyruvate: A new strategy for inhibition of glycolytic enzymes in Leishmania amazonensis

The compound 3-bromopyruvate (3-BrPA) is well-known and studies from several researchers have demonstrated its involvement in tumorigenesis. It is an analogue of pyruvic acid that inhibits ATP synthesis by inhibiting enzymes from the glycolytic pathway and oxidative phosphorylation. In this work, we...

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Published in:Experimental parasitology 2021-10, Vol.229, p.108154-108154, Article 108154
Main Authors: Gomes, Marta Teixeira, Paes-Vieira, Lisvane, Gomes-Vieira, André Luiz, Cosentino-Gomes, Daniela, da Silva, Ana Paula Pereira, Giarola, Naira Ligia Lima, Da Silva, Daniel, Sola-Penna, Mauro, Galina, Antonio, Meyer-Fernandes, José Roberto
Format: Article
Language:English
Subjects:
3-Bromopyruvate
Energy metabolism
Glycolytic enzymes
Leishmania amazonensis
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Summary:The compound 3-bromopyruvate (3-BrPA) is well-known and studies from several researchers have demonstrated its involvement in tumorigenesis. It is an analogue of pyruvic acid that inhibits ATP synthesis by inhibiting enzymes from the glycolytic pathway and oxidative phosphorylation. In this work, we investigated the effect of 3-BrPA on energy metabolism of L. amazonensis. In order to verify the effect of 3-BrPA on L. amazonensis glycolysis, we measured the activity level of three glycolytic enzymes located at different points of the pathway: (i) glucose kinases, step 1, (ii) glyceraldehyde 3-phosphate dehydrogenase (GAPDH), step 6, and (iii) enolase, step 9. 3-BrPA, in a dose-dependent manner, significantly reduced the activity levels of all the enzymes. In addition, 3-BrPA treatment led to a reduction in the levels of phosphofruto-1-kinase (PFK) protein, suggesting that the mode of action of 3-BrPA involves the downregulation of some glycolytic enzymes. Measurement of ATP levels in promastigotes of L. amazonensis showed a significant reduction in ATP generation. The O2 consumption was also significantly inhibited in promastigotes, confirming the energy depletion effect of 3-BrPA. When 3-BrPA was added to the cells at the beginning of growth cycle, it significantly inhibited L. amazonensis proliferation in a dose-dependent manner. Furthermore, the ability to infect macrophages was reduced by approximately 50% when promastigotes were treated with 3-BrPA. Taken together, these studies corroborate with previous reports which suggest 3-BrPA as a potential drug against pathogenic microorganisms that are reliant on glucose catabolism for ATP supply. [Display omitted] •L. amazonensis glycolysis is inhibited by 3-BrPA.•3-BrPA has a strong effect on L. amazonensis ATP synthesis.•3-BrPA inhibits O2 consumption of L. amazonensis.•Promastigotes proliferation is inhibited by 3-BrPA.•L. amazonensis infectivity is reduced by 3-BrPA.
ISSN:0014-4894
1090-2449
DOI:10.1016/j.exppara.2021.108154