Andrea Cillingova, Renata Toth, Anna Mojakova, Igor Zeman, Romana Vrzonova, Barbara Sivakova, Peter Barath, Martina Nebohacova, Zuzana Klepcova, Filip Brazdovic, Hana Lichancova, Viktoria Hodorova, Brona Brejova, Tomas Vinar, Sofia Mutalova, Veronika Vozarikova, Giacomo Mutti, Lubomir Tomaska, Atilla Gacser, Toni Gabaldon, Jozef Nosek. Transcriptome and proteome profiling reveals complex adaptations of Candidaparapsilosis cells assimilating hydroxyaromatic carbon sources. PLoS Genetics, 18(3):e1009815. 2022.

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Many fungal species utilize hydroxyderivatives of benzene and benzoic acid as
carbon sources. The yeast Candida parapsilosis metabolizes these compounds via
the 3-oxoadipate and gentisate pathways, whose components are encoded by two
metabolic gene clusters. In this study, we determine the chromosome level
assembly of the C. parapsilosis strain CLIB214 and use it for transcriptomic and 
proteomic investigation of cells cultivated on hydroxyaromatic substrates. We
demonstrate that the genes coding for enzymes and plasma membrane transporters
involved in the 3-oxoadipate and gentisate pathways are highly upregulated and
their expression is controlled in a substrate-specific manner. However,
regulatory proteins involved in this process are not known. Using the knockout
mutants, we show that putative transcriptional factors encoded by the genes OTF1 
and GTF1 located within these gene clusters function as transcriptional
activators of the 3-oxoadipate and gentisate pathway, respectively. We also show 
that the activation of both pathways is accompanied by upregulation of genes for 
the enzymes involved in beta-oxidation of fatty acids, glyoxylate cycle, amino
acid metabolism, and peroxisome biogenesis. Transcriptome and proteome profiles
of the cells grown on 4-hydroxybenzoate and 3-hydroxybenzoate, which are
metabolized via the 3-oxoadipate and gentisate pathway, respectively, reflect
their different connection to central metabolism. Yet we find that the expression
profiles differ also in the cells assimilating 4-hydroxybenzoate and
hydroquinone, which are both metabolized in the same pathway. This finding is
consistent with the phenotype of the Otf1p-lacking mutant, which exhibits
impaired growth on hydroxybenzoates, but still utilizes hydroxybenzenes, thus
indicating that additional, yet unidentified transcription factor could be
involved in the 3-oxoadipate pathway regulation. Moreover, we propose that
bicarbonate ions resulting from decarboxylation of hydroxybenzoates also
contribute to differences in the cell responses to hydroxybenzoates and
hydroxybenzenes. Finally, our phylogenetic analysis highlights evolutionary paths
leading to metabolic adaptations of yeast cells assimilating hydroxyaromatic