{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:46:11Z","timestamp":1760147171094,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T00:00:00Z","timestamp":1673568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MCTI\/CNPq (Minist\u00e9rio da Ci\u00eancia e Tecnologia\/Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico)","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"FNDCT (Fundo Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico)","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"FAPEG (Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de Goi\u00e1s)","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"CAPES (Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"FINEP (Financiadora de Estudos e Projetos)","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"PRONEX (Programa de Apoio a N\u00facleos de Excel\u00eancia)","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"INCT-IPH (Instituto Nacional de Ci\u00eancia e Tecnologia de Estrat\u00e9gias de Intera\u00e7\u00e3o Pat\u00f3geno-Hospedeiro)","award":["001"],"award-info":[{"award-number":["001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>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 \u00df-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.<\/jats:p>","DOI":"10.3390\/jof9010108","type":"journal-article","created":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T01:30:26Z","timestamp":1673573426000},"page":"108","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["New Methylcitrate Synthase Inhibitor Induces Proteolysis, Lipid Degradation and Pyruvate Excretion in Paracoccidioides brasiliensis"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2094-6042","authenticated-orcid":false,"given":"Olivia Basso","family":"Rocha","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Biology, Institute of Biological Sciences, Federal University of Goi\u00e1s, Avenida Esperan\u00e7a, s\/n, ICB2, Sala 206, Goi\u00e2nia 74690-900, GO, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5350-7313","authenticated-orcid":false,"given":"Kleber Santiago","family":"Freitas e Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Institute of Biological Sciences, Federal University of Goi\u00e1s, Avenida Esperan\u00e7a, s\/n, ICB2, Sala 206, Goi\u00e2nia 74690-900, GO, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thaynara Gonzaga","family":"Santos","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Institute of Biological Sciences, Federal University of Goi\u00e1s, Avenida Esperan\u00e7a, s\/n, ICB2, Sala 206, Goi\u00e2nia 74690-900, GO, Brazil"},{"name":"Institute of Tropical Pathology and Public Health, Federal University of Goi\u00e1s, Goi\u00e2nia 74690-900, GO, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1031-1465","authenticated-orcid":false,"given":"Dayane","family":"Moraes","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Institute of Biological Sciences, Federal University of Goi\u00e1s, Avenida Esperan\u00e7a, s\/n, ICB2, Sala 206, Goi\u00e2nia 74690-900, GO, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leandro do Prado","family":"Assun\u00e7\u00e3o","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Institute of Biological Sciences, Federal University of Goi\u00e1s, Avenida Esperan\u00e7a, s\/n, ICB2, Sala 206, Goi\u00e2nia 74690-900, GO, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7754-4047","authenticated-orcid":false,"given":"Alexandre Melo","family":"Bail\u00e3o","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Institute of Biological Sciences, Federal University of Goi\u00e1s, Avenida Esperan\u00e7a, s\/n, ICB2, Sala 206, Goi\u00e2nia 74690-900, GO, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5378-9840","authenticated-orcid":false,"given":"C\u00e9lia Maria de Almeida","family":"Soares","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Institute of Biological Sciences, Federal University of Goi\u00e1s, Avenida Esperan\u00e7a, s\/n, ICB2, Sala 206, Goi\u00e2nia 74690-900, GO, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5482-8036","authenticated-orcid":false,"given":"Maristela","family":"Pereira","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Institute of Biological Sciences, Federal University of Goi\u00e1s, Avenida Esperan\u00e7a, s\/n, ICB2, Sala 206, Goi\u00e2nia 74690-900, GO, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,13]]},"reference":[{"key":"ref_1","first-page":"1319","article-title":"Paracoccidioides-Host Interaction: An Overview on Recent Advances in the Paracoccidioidomycosis","volume":"6","author":"Assato","year":"2015","journal-title":"Front. 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