Ergothioneine Biosynthesis and Functionality in the Opportunistic Fungal Pathogen, Aspergillus fumigatus

• Published in: Scientific reports Vol. 6; no. 1; p. 35306
• Main Authors: Sheridan, Kevin J., Lechner, Beatrix Elisabeth, Keeffe, Grainne O’, Keller, Markus A., Werner, Ernst R., Lindner, Herbert, Jones, Gary W., Haas, Hubertus, Doyle, Sean
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.10.2016; Nature Publishing Group
• Subjects: 45/41; 45/70; 631/326/193; 631/45/475; 82/58; Antioxidants; Antioxidants - chemistry; Aspergillus fumigatus - genetics; Aspergillus fumigatus - metabolism; Biosynthesis; Carbon-Oxygen Lyases - metabolism; Clonal deletion; Composting; Ergothioneine - biosynthesis; Ferric Compounds - chemistry; Ferrichrome - analogs & derivatives; Ferrichrome - metabolism; Fungal Proteins - genetics; Fungal Proteins - metabolism; Gene Deletion; Genetic Complementation Test; Gliotoxin; Gliotoxin - chemistry; Glutathione - metabolism; Heavy metals; Histidine; Histidine - chemistry; Homeostasis; Humanities and Social Sciences; Hydrogen Peroxide - chemistry; Hydroxamic Acids - chemistry; Intracellular; Lyases - metabolism; Menadione; Metals, Heavy - chemistry; multidisciplinary; Opportunist infection; Oxidation-Reduction; Oxidative Stress; Pathogens; Proteomics - methods; Reactive oxygen species; Reactive Oxygen Species - metabolism; Science; Siderophores - chemistry; Triacetylfusarinine C; Vitamin K 3 - chemistry; Yes-associated protein
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep35306

Ergothioneine (EGT; 2-mercaptohistidine trimethylbetaine) is a trimethylated and sulphurised histidine derivative which exhibits antioxidant properties. Here we report that deletion of Aspergillus fumigatus egtA (AFUA_2G15650), which encodes a trimodular enzyme, abrogated EGT biosynthesis in this opportunistic pathogen. EGT biosynthetic deficiency in A. fumigatus significantly reduced resistance to elevated H 2 O 2 and menadione, respectively, impaired gliotoxin production and resulted in attenuated conidiation. Quantitative proteomic analysis revealed substantial proteomic remodelling in Δ egtA compared to wild-type under both basal and ROS conditions, whereby the abundance of 290 proteins was altered. Specifically, the reciprocal differential abundance of cystathionine γ-synthase and β-lyase, respectively, influenced cystathionine availability to effect EGT biosynthesis. A combined deficiency in EGT biosynthesis and the oxidative stress response regulator Yap1, which led to extreme oxidative stress susceptibility, decreased resistance to heavy metals and production of the extracellular siderophore triacetylfusarinine C and increased accumulation of the intracellular siderophore ferricrocin. EGT dissipated H 2 O 2 in vitro , and elevated intracellular GSH levels accompanied abrogation of EGT biosynthesis. EGT deficiency only decreased resistance to high H 2 O 2 levels which suggests functionality as an auxiliary antioxidant, required for growth at elevated oxidative stress conditions. Combined, these data reveal new interactions between cellular redox homeostasis, secondary metabolism and metal ion homeostasis.