Ergothioneine Biosynthesis and Functionality in the Opportunistic Fungal Pathogen, Aspergillus fumigatus
Open accessAbstract
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 2in 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.
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In M. tuberculosis and other mycobacteria, other actinobacteria and fungi, ERG can have a role as an antioxidant and act as a buffer against reductive stress.
“In M. tuberculosis and other mycobacteria(254), and also in other actinobacteria(255) and in fungi(247,256,257), it is clear that ERG can have a role as an antioxidant(66,258–260) and also act as a buffer against reductive stress(261).”
From The biology of ergothioneine, an antioxidant nutraceutical (2020) · cites this paper as [257]
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Schrettl, M., Bignell, E., Kragl, C., Joechl, C., Rogers, T., Arst, H. N., Haynes, K., & Haas, H. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20041242 · Cited by 493 · see citing works
Self-citationDistinct Roles for Intra- and Extracellular Siderophores during Aspergillus fumigatus Infection
Schrettl, M., Bignell, E., Kragl, C., Sabiha, Y., Loss, O., Eisendle, M., Wallner, A., Arst, H. N., Haynes, K., & Haas, H. (2007) · PLoS Pathogens · doi:10.1371/journal.ppat.0030128 · Cited by 405 · see citing works
Self-citationFungal siderophore metabolism with a focus on <i>Aspergillus fumigatus</i>
Haas, H. (2014) · Nat. Prod. Rep. · doi:10.1039/c4np00071d · Cited by 324 · see citing works
Self-citationThe evolutionary history of the genes involved in the biosynthesis of the antioxidant ergothioneine
Jones, G. W., Doyle, S., & Fitzpatrick, D. A. (2014) · Gene · doi:10.1016/j.gene.2014.07.065 · Cited by 79 · see citing works
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The biology of ergothioneine, an antioxidant nutraceutical
Borodina, I., Kenny, L. C., McCarthy, C. M., Paramasivan, K., Pretorius, E., Roberts, T. J., van der Hoek, S. A., & Kell, D. B. (2020) · Nutrition Research Reviews · doi:10.1017/s0954422419000301 · Cited by 296 · see citing works
“tuberculosis and other mycobacteria(254), and also in other actinobacteria(255) and in fungi(247,256,257), it is clear that ERG can have a role as an antioxidant(66,258–260) and also act”
BackgroundErgothioneine Antioxidant Function: From Chemistry to Cardiovascular Therapeutic Potential
Servillo, L., D'Onofrio, N., & Balestrieri, M. L. (2017) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000000464 · Cited by 81 · see citing works
Regeneration of ergothioneine after reaction with singlet oxygen
Oumari, M., Goldfuss, B., Stoffels, C., Schmalz, H.-G., & Gründemann, D. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.01.043 · Cited by 39 · see citing works
- Authors
- Sheridan, K. J., Lechner, B. E., Keeffe, G. O., Keller, M. A., Werner, E. R., Lindner, H., Jones, G. W., Haas, H., & Doyle, S.
- Affiliations
- National University of Ireland, Maynooth (IE)
- Innsbruck Medical University (AT)
- Corresponding author
- Haas, Hubertus
- ORCID
- Venue
- Scientific Reports
- Published
- 2016-10-17
- Volume
- 6
- Issue
- 1
- Pages
- 35306-35306
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5066259
- OpenAlex
- W2534532732
- Cited by
- 73
- References
- 4
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 3 · 2023: 10 · 2022: 9 · 2021: 3 · 2020: 8 · 2019: 10 · 2018: 4 · 2017: 10 · 2015: 1
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Leeds Beckett Repository (Leeds Beckett University) (acceptedVersion)
- Maynooth University ePrints and eTheses Archive (Maynooth University) (acceptedVersion)
- Funders
- Science Foundation Ireland (11/PI/1188, RFP/GEN/F571)
- Austrian Science Fund (I 1346)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- ergothioneine biosynthesis, Aspergillus fumigatus, oxidative stress resistance, hydrogen peroxide, menadione, conidiation, cystathionine gamma-synthase, beta-lyase, YAP, heavy metal resistance, ferricrocin, siderophores, glutathione, redox homeostasis, secondary metabolism, metal homeostasis
- MeSH terms
- Antioxidants, Aspergillus fumigatus, Ergothioneine, Ferric Compounds, Ferrichrome, Fungal Proteins, Genetic Complementation Test, Gliotoxin, Glutathione, Histidine, Hydrogen Peroxide, Hydroxamic Acids, Lyases, Oxidation-Reduction, Siderophores, Gene Deletion, Reactive Oxygen Species, Oxidative Stress, Metals, Heavy, Carbon-Oxygen Lyases, Vitamin K 3, Proteomics
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