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New Methylcitrate Synthase Inhibitor Induces Proteolysis, Lipid Degradation and Pyruvate Excretion in Paracoccidioides brasiliensis

Background: Paracoccidioidomycosis is a systemic mycosis caused by the inhalation of conidia of the genus Paracoccidioides. During the infectious process, fungal cells use several carbon sources, leading to the production of propionyl-CoA. The latter is metabolized by the methylcitrate synthase, a k...

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Autores principales: Rocha, Olivia Basso, Freitas e Silva, Kleber Santiago, Santos, Thaynara Gonzaga, Moraes, Dayane, Assunção, Leandro do Prado, Bailão, Alexandre Melo, Soares, Célia Maria de Almeida, Pereira, Maristela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865517/
https://www.ncbi.nlm.nih.gov/pubmed/36675929
http://dx.doi.org/10.3390/jof9010108
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author Rocha, Olivia Basso
Freitas e Silva, Kleber Santiago
Santos, Thaynara Gonzaga
Moraes, Dayane
Assunção, Leandro do Prado
Bailão, Alexandre Melo
Soares, Célia Maria de Almeida
Pereira, Maristela
author_facet Rocha, Olivia Basso
Freitas e Silva, Kleber Santiago
Santos, Thaynara Gonzaga
Moraes, Dayane
Assunção, Leandro do Prado
Bailão, Alexandre Melo
Soares, Célia Maria de Almeida
Pereira, Maristela
author_sort Rocha, Olivia Basso
collection PubMed
description Background: Paracoccidioidomycosis is a systemic mycosis caused by the inhalation of conidia of the genus Paracoccidioides. During the infectious process, fungal cells use several carbon sources, leading to the production of propionyl-CoA. The latter is metabolized by the methylcitrate synthase, a key enzyme of the methylcitrate cycle. We identified an inhibitor compound (ZINC08964784) that showed antifungal activity against P. brasiliensis. Methods: This work aimed to understand the fungal metabolic response of P. brasiliensis cells exposed to ZINC08964784 through a proteomics approach. We used a glucose-free medium supplemented with propionate in order to simulate the environment found by the pathogen during the infection. We performed pyruvate dosage, proteolytic assay, dosage of intracellular lipids and quantification of reactive oxygen species in order to validate the proteomic results. Results: The proteomic analysis indicated that the fungal cells undergo a metabolic shift due to the inhibition of the methylcitrate cycle and the generation of reactive species. Proteolytic enzymes were induced, driving amino acids into degradation for energy production. In addition, glycolysis and the citric acid cycle were down-regulated while ß-oxidation was up-regulated. The accumulation of pyruvate and propionyl-CoA led the cells to a state of oxidative stress in the presence of ZINC08964784. Conclusions: The inhibition of methylcitrate synthase caused by the compound promoted a metabolic shift in P. brasiliensis damaging energy production and generating oxidative stress. Hence, the compound is a promising alternative for developing new strategies of therapies against paracoccidioidomycosis.
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spelling pubmed-98655172023-01-22 New Methylcitrate Synthase Inhibitor Induces Proteolysis, Lipid Degradation and Pyruvate Excretion in Paracoccidioides brasiliensis Rocha, Olivia Basso Freitas e Silva, Kleber Santiago Santos, Thaynara Gonzaga Moraes, Dayane Assunção, Leandro do Prado Bailão, Alexandre Melo Soares, Célia Maria de Almeida Pereira, Maristela J Fungi (Basel) Article Background: Paracoccidioidomycosis is a systemic mycosis caused by the inhalation of conidia of the genus Paracoccidioides. During the infectious process, fungal cells use several carbon sources, leading to the production of propionyl-CoA. The latter is metabolized by the methylcitrate synthase, a key enzyme of the methylcitrate cycle. We identified an inhibitor compound (ZINC08964784) that showed antifungal activity against P. brasiliensis. Methods: This work aimed to understand the fungal metabolic response of P. brasiliensis cells exposed to ZINC08964784 through a proteomics approach. We used a glucose-free medium supplemented with propionate in order to simulate the environment found by the pathogen during the infection. We performed pyruvate dosage, proteolytic assay, dosage of intracellular lipids and quantification of reactive oxygen species in order to validate the proteomic results. Results: The proteomic analysis indicated that the fungal cells undergo a metabolic shift due to the inhibition of the methylcitrate cycle and the generation of reactive species. Proteolytic enzymes were induced, driving amino acids into degradation for energy production. In addition, glycolysis and the citric acid cycle were down-regulated while ß-oxidation was up-regulated. The accumulation of pyruvate and propionyl-CoA led the cells to a state of oxidative stress in the presence of ZINC08964784. Conclusions: The inhibition of methylcitrate synthase caused by the compound promoted a metabolic shift in P. brasiliensis damaging energy production and generating oxidative stress. Hence, the compound is a promising alternative for developing new strategies of therapies against paracoccidioidomycosis. MDPI 2023-01-13 /pmc/articles/PMC9865517/ /pubmed/36675929 http://dx.doi.org/10.3390/jof9010108 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rocha, Olivia Basso
Freitas e Silva, Kleber Santiago
Santos, Thaynara Gonzaga
Moraes, Dayane
Assunção, Leandro do Prado
Bailão, Alexandre Melo
Soares, Célia Maria de Almeida
Pereira, Maristela
New Methylcitrate Synthase Inhibitor Induces Proteolysis, Lipid Degradation and Pyruvate Excretion in Paracoccidioides brasiliensis
title New Methylcitrate Synthase Inhibitor Induces Proteolysis, Lipid Degradation and Pyruvate Excretion in Paracoccidioides brasiliensis
title_full New Methylcitrate Synthase Inhibitor Induces Proteolysis, Lipid Degradation and Pyruvate Excretion in Paracoccidioides brasiliensis
title_fullStr New Methylcitrate Synthase Inhibitor Induces Proteolysis, Lipid Degradation and Pyruvate Excretion in Paracoccidioides brasiliensis
title_full_unstemmed New Methylcitrate Synthase Inhibitor Induces Proteolysis, Lipid Degradation and Pyruvate Excretion in Paracoccidioides brasiliensis
title_short New Methylcitrate Synthase Inhibitor Induces Proteolysis, Lipid Degradation and Pyruvate Excretion in Paracoccidioides brasiliensis
title_sort new methylcitrate synthase inhibitor induces proteolysis, lipid degradation and pyruvate excretion in paracoccidioides brasiliensis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865517/
https://www.ncbi.nlm.nih.gov/pubmed/36675929
http://dx.doi.org/10.3390/jof9010108
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