| Summary: | Species of the genus <i>Paracoccidioides</i> cause a systemic infection in human patients. Yeast cells of <i>Paracoccidioides</i> spp. produce melanin in the presence of L-dihydroxyphenylalanine and during infection, which may impact the pathogen’s survival in the host. To better understand the metabolic changes that occur in melanized <i>Paracoccidioides</i> spp. cells, a proteomic approach was performed to compare melanized and non-melanized <i>Paracoccidioides brasiliensis</i> and <i>Paracoccidioides lutzii</i> yeast cells. Melanization was induced using L-dihydroxyphenylalanine as a precursor, and quantitative proteomics were performed using reversed-phase nano-chromatography coupled to high-resolution mass spectrometry. When comparing melanized versus non-melanized cells, 1006 and 582 differentially abundant/detected proteins were identified for <i>P. brasiliensis</i> and <i>P. lutzii</i>, respectively. Functional enrichment and comparative analysis revealed 30 important KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways in melanized <i>P. brasiliensis</i> and 18 in <i>P. lutzii</i>, while differentially abundant proteins from non-melanized cells from these species were involved in 21 and 25 enriched pathways, respectively. Melanized cells presented an abundance of additional virulence-associated proteins, such as phospholipase, proteases, superoxide dis-mutases, heat-shock proteins, adhesins, and proteins related to vesicular transport. The results suggest that L-dihydroxyphenylalanine increases the virulence of <i>Paracoccidioides</i> spp. through complex mechanisms involving not only melanin but other virulence factors as well.
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