A multi-omics analysis unveils functional and regulatory links between hydroxybenzene and aromatic amino acid metabolism in Candida albicans.

The fungus Candida albicans is a frequent colonizer of humans but also an opportunistic pathogen causing superficial to severe infections, especially in vulnerable individuals. Its broad metabolic flexibility is key for the fungal adaptation to host environments, evasion from immune attack, and virulence. Amino acid metabolism and homeostasis, in particular, are critical for fungal fitness-illustrated by a rapid metabolic shift in response to amino acid starvation to restore intracellular metabolic balance. To investigate the cellular mechanisms underlying such compensatory metabolic processes, we performed data-driven genome-scale metabolic modeling based on transcriptional metabolic profiles of amino acid-starved cells to identify condition-specific fungal metabolic fluxes and pathway activities specific to cellular response to amino acid starvation. Most prominently, we predicted altered activity of the shikimate pathway upon amino acid limitation and identified a simultaneous induction of aromatic amino acid (AAA) biosynthesis and a metabolic gene cluster required for the catabolism of hydroxybenzenes. Further phenotypic and transcriptional analyses not only verified the transcription factor Zcf25 as the central regulator of the catechol-branch of this pathway, but also condition-specific co-regulation of AAA and hydroxybenzene metabolism mediated by Zcf25 and the transcriptional regulator of amino acid metabolism Stp2. These findings propose a so far unknown metabolic link between amino acid and hydroxybenzene metabolism in C. albicans, therewith adding another layer to its metabolic plasticity.