Cargando…

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

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 op...

Descripción completa

Detalles Bibliográficos
Autores principales: Sheridan, Kevin J., Lechner, Beatrix Elisabeth, Keeffe, Grainne O’, Keller, Markus A., Werner, Ernst R., Lindner, Herbert, Jones, Gary W., Haas, Hubertus, Doyle, Sean
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066259/
https://www.ncbi.nlm.nih.gov/pubmed/27748436
http://dx.doi.org/10.1038/srep35306
_version_ 1782460454053871616
author Sheridan, Kevin J.
Lechner, Beatrix Elisabeth
Keeffe, Grainne O’
Keller, Markus A.
Werner, Ernst R.
Lindner, Herbert
Jones, Gary W.
Haas, Hubertus
Doyle, Sean
author_facet Sheridan, Kevin J.
Lechner, Beatrix Elisabeth
Keeffe, Grainne O’
Keller, Markus A.
Werner, Ernst R.
Lindner, Herbert
Jones, Gary W.
Haas, Hubertus
Doyle, Sean
author_sort Sheridan, Kevin J.
collection PubMed
description 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 ΔegtA 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.
format Online
Article
Text
id pubmed-5066259
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-50662592016-10-26 Ergothioneine Biosynthesis and Functionality in the Opportunistic Fungal Pathogen, Aspergillus fumigatus Sheridan, Kevin J. Lechner, Beatrix Elisabeth Keeffe, Grainne O’ Keller, Markus A. Werner, Ernst R. Lindner, Herbert Jones, Gary W. Haas, Hubertus Doyle, Sean Sci Rep Article 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 ΔegtA 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. Nature Publishing Group 2016-10-17 /pmc/articles/PMC5066259/ /pubmed/27748436 http://dx.doi.org/10.1038/srep35306 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Sheridan, Kevin J.
Lechner, Beatrix Elisabeth
Keeffe, Grainne O’
Keller, Markus A.
Werner, Ernst R.
Lindner, Herbert
Jones, Gary W.
Haas, Hubertus
Doyle, Sean
Ergothioneine Biosynthesis and Functionality in the Opportunistic Fungal Pathogen, Aspergillus fumigatus
title Ergothioneine Biosynthesis and Functionality in the Opportunistic Fungal Pathogen, Aspergillus fumigatus
title_full Ergothioneine Biosynthesis and Functionality in the Opportunistic Fungal Pathogen, Aspergillus fumigatus
title_fullStr Ergothioneine Biosynthesis and Functionality in the Opportunistic Fungal Pathogen, Aspergillus fumigatus
title_full_unstemmed Ergothioneine Biosynthesis and Functionality in the Opportunistic Fungal Pathogen, Aspergillus fumigatus
title_short Ergothioneine Biosynthesis and Functionality in the Opportunistic Fungal Pathogen, Aspergillus fumigatus
title_sort ergothioneine biosynthesis and functionality in the opportunistic fungal pathogen, aspergillus fumigatus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066259/
https://www.ncbi.nlm.nih.gov/pubmed/27748436
http://dx.doi.org/10.1038/srep35306
work_keys_str_mv AT sheridankevinj ergothioneinebiosynthesisandfunctionalityintheopportunisticfungalpathogenaspergillusfumigatus
AT lechnerbeatrixelisabeth ergothioneinebiosynthesisandfunctionalityintheopportunisticfungalpathogenaspergillusfumigatus
AT keeffegrainneo ergothioneinebiosynthesisandfunctionalityintheopportunisticfungalpathogenaspergillusfumigatus
AT kellermarkusa ergothioneinebiosynthesisandfunctionalityintheopportunisticfungalpathogenaspergillusfumigatus
AT wernerernstr ergothioneinebiosynthesisandfunctionalityintheopportunisticfungalpathogenaspergillusfumigatus
AT lindnerherbert ergothioneinebiosynthesisandfunctionalityintheopportunisticfungalpathogenaspergillusfumigatus
AT jonesgaryw ergothioneinebiosynthesisandfunctionalityintheopportunisticfungalpathogenaspergillusfumigatus
AT haashubertus ergothioneinebiosynthesisandfunctionalityintheopportunisticfungalpathogenaspergillusfumigatus
AT doylesean ergothioneinebiosynthesisandfunctionalityintheopportunisticfungalpathogenaspergillusfumigatus