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    Structural, mechanistic and functional insight into gliotoxin bis-thiomethylation in Aspergillus fumigatus


    Dolan, Stephen K. and Bock, Tobias and Hering, Vanessa and Owens, Rebecca A. and Jones, Gary W. and Blankenfeldt, Wulf and Doyle, Sean (2017) Structural, mechanistic and functional insight into gliotoxin bis-thiomethylation in Aspergillus fumigatus. Open Biology, 7 (2). ISSN 2046-2441

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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. Self-resistance against gliotoxin is effected by the gliotoxin oxidase GliT, and attenuation of gliotoxin biosynthesis is catalysed by gliotoxin S-methyltransferase GtmA. Here we describe the X-ray crystal structures of GtmA-apo (1.66 Å), GtmA complexed to S-adenosylhomocysteine (1.33 Å) and GtmA complexed to S-adenosylmethionine (2.28 Å), providing mechanistic insights into this important biotransformation. We further reveal that simultaneous elimination of the ability of A. fumigatus to dissipate highly reactive dithiol gliotoxin, via deletion of GliT and GtmA, results in the most significant hypersensitivity to exogenous gliotoxin observed to date. Indeed, quantitative proteomic analysis of ΔgliT::ΔgtmA reveals an uncontrolled over-activation of the gli-cluster upon gliotoxin exposure. The data presented herein reveal, for the first time, the extreme risk associated with intracellular dithiol gliotoxin biosynthesis—in the absence of an efficient dismutation capacity. Significantly, a previously concealed protective role for GtmA and functionality of ETP bis-thiomethylation as an ancestral protection strategy against dithiol compounds is now evident.

    Item Type: Article
    Additional Information: © 2017 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited. Cite as: Dolan SK, Bock T, Hering V, Owens RA, Jones GW, Blankenfeldt W, Doyle S. 2017 Structural, mechanistic and functional insight into gliotoxin bis-thiomethylation in Aspergillus fumigatus. Open Biol. 7: 160292. http://dx.doi.org/10.1098/rsob.160292
    Keywords: methyltransferase; NRPS; quantitative proteomics; Aspergillus;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 10908
    Identification Number: https://doi.org/10.1098/rsob.160292
    Depositing User: Rebecca Owens
    Date Deposited: 01 Jul 2019 16:57
    Journal or Publication Title: Open Biology
    Publisher: The Royal Society
    Refereed: Yes
    URI:

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