Abstract
Fungal sulfur uptake is required for incorporation into the sidechains of the amino acids cysteine and methionine, and is also essential for the biosynthesis of the antioxidant glutathione (GSH), S-adenosylmethionine (SAM), the key source of methyl groups in cellular transmethylation reactions, and S-adenosylhomocysteine (SAH). Biosynthesis of redox-active gliotoxin in the opportunistic fungal pathogen Aspergillus fumigatus has been elucidated over the past 10 years. Some fungi which produce gliotoxin-like molecular species have undergone unexpected molecular rewiring to accommodate this high-risk biosynthetic process. Specific disruption of gliotoxin biosynthesis, via deletion of gliK, which encodes a γ-glutamyl cyclotransferase, leads to elevated intracellular antioxidant, ergothioneine (EGT), levels, and confirms crosstalk between the biosynthesis of both sulfur-containing moieties. Gliotoxin is ultimately formed by gliotoxin oxidoreductase GliT-mediated oxidation of dithiol gliotoxin (DTG). In fact, DTG is a substrate for both GliT and a bis-thiomethyltransferase, GtmA. GtmA converts DTG to bisdethiobis(methylthio)gliotoxin (BmGT), using 2 mol SAM and resultant SAH must be re-converted to SAM via the action of the Methyl/Met cycle. In the absence of GliT, DTG fluxes via GtmA to BmGT, which results in both SAM depletion and SAH overproduction. Thus, the negative regulation of gliotoxin biosynthesis via GtmA must be counter-balanced by GliT activity to avoid Methyl/Met cycle dysregulation, SAM depletion and trans consequences on global cellular biochemistry in A. fumigatus. DTG also possesses potent Zn2+ chelation properties which positions this sulfur-containing metabolite as a putative component of the Zn2+ homeostasis system within fungi. EGT plays an essential role in high-level redox homeostasis and its presence requires significant consideration in future oxidative stress studies in pathogenic filamentous fungi. In certain filamentous fungi, sulfur is additionally indirectly required for the formation of EGT and the disulfide-bridge containing non-ribosomal peptide, gliotoxin, and related epipolythiodioxopiperazines. Ultimately, interference with emerging sulfur metabolite functionality may represent a new strategy for antifungal drug development.
Highlights
Sulfur is an essential element that is incorporated into various cellular metabolites and used for multiple metabolic processes in fungi, including the proteogenic amino acids cysteine (Cys) and methionine (Met), oxidative stress defense [glutathione (GSH) and ergothioneine (EGT)], methylation [S-adenosylmethionine (SAM)], epipolythiodioxopiperazine (ETP) toxin biosynthesis and iron metabolism (Fe–S clusters) (Davis et al, 2011; Struck et al, 2012; Amich et al, 2013; Sheridan et al, 2016)
Regulation of intracellular SAM/SAH levels is critical, as disruption can adversely affect tightly regulated gene expression, and potentially impede cell growth. How this is achieved in fungi capable of gliotoxin, BmGT and EGT biosynthesis (Cramer et al, 2006; Dolan et al, 2014; Sheridan et al, 2016), all of which are highly dependent on SAM utilization, and concomitant SAH generation (Owens et al, 2015), is only just becoming apparent – and potentially represents a new direction in the search for antifungal drug targets
Gliotoxin, or specific reactions required for its biosynthesis, have been shown to influence the formation of other sulfur-containing metabolites, like EGT (Gallagher et al, 2012; Sheridan et al, 2016), and the activity of gliotoxin against fungi is revealing even further interactions within biological systems- most recently involving zinc homeostasis (Vicentefranqueira et al, 2018)
Summary
Sulfur is indirectly required for the formation of EGT and the disulfide-bridge containing non-ribosomal peptide, gliotoxin, and related epipolythiodioxopiperazines. Interference with emerging sulfur metabolite functionality may represent a new strategy for antifungal drug development
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