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    Dysregulated gliotoxin biosynthesis attenuates the production of unrelated biosynthetic gene cluster-encoded metabolites in Aspergillus fumigatus


    Doyle, Sean and Jones, Gary W. and Dolan, Stephen K. (2018) Dysregulated gliotoxin biosynthesis attenuates the production of unrelated biosynthetic gene cluster-encoded metabolites in Aspergillus fumigatus. Fungal Biology, 122. pp. 214-221. ISSN 1878-6146

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    Abstract

    Gliotoxin is an epipolythiodioxopiperazine (ETP) class toxin, contains a disulfide bridge that mediates its toxic effects via redox cycling and is produced by the opportunistic fungal pathogen Aspergillus fumigatus. The gliotoxin bis-thiomethyltransferase, GtmA, attenuates gliotoxin biosynthesis in A. fumigatus by conversion of dithiol gliotoxin to bis-thiomethylgliotoxin (BmGT). Here we show that disruption of dithiol gliotoxin bis-thiomethylation functionality in A. fumigatus results in significant remodelling of the A. fumigatus secondary metabolome upon extended culture. RP-HPLC and LCeMS/MS analysis revealed the reduced production of a plethora of unrelated biosynthetic gene cluster-encoded metabolites, including pseurotin A, fumagillin, fumitremorgin C and tryprostatin B, occurs in A. fumigatus DgtmA upon extended incubation. Parallel quantitative proteomic analysis of A. fumigatus wild-type and DgtmA during extended culture revealed cognate abundance alteration of proteins encoded by relevant biosynthetic gene clusters, allied to multiple alterations in hypoxia-related proteins. The data presented herein reveal a previously concealed functionality of GtmA in facilitating the biosynthesis of other BGC-encoded metabolites produced by A. fumigatus.

    Item Type: Article
    Keywords: BGC; Fungal proteomics; LC–MS; Metabolomics; Methyltransferase; NRPS;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 12397
    Identification Number: https://doi.org/10.1016/j.funbio.2017.12.007
    Depositing User: Dr. Sean Doyle
    Date Deposited: 10 Feb 2020 17:19
    Journal or Publication Title: Fungal Biology
    Publisher: Elsevier
    Refereed: Yes
    URI:

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