Supplementary material from "Structural, mechanistic and functional insight into gliotoxin <i>bis</i>-thiomethylation in <i>Aspergillus fumigatus</i>"

Published on 2017-01-24T16:10:59Z (GMT) by
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 <i>Aspergillus fumigatus</i>. Self-resistance against gliotoxin is effected by the gliotoxin oxidase GliT, and attenuation of gliotoxin biosynthesis is catalysed by gliotoxin <i>S</i>-methyltransferase GtmA. Here we describe the X-ray crystal structures of GtmA-apo (1.66 Å), GtmA complexed to <i>S</i>-adenosylhomocysteine (1.33 Å) and GtmA complexed to <i>S</i>-adenosylmethionine (2.28 Å), providing mechanistic insights into this important biotransformation. We further reveal that simultaneous elimination of the ability of <i>A. fumigatus</i> 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 Δ<i>gliT</i>::Δ<i>gtmA</i> reveals an uncontrolled over-activation of the <i>gli</i>-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 <i>bis</i>-thiomethylation as an ancestral protection strategy against dithiol compounds is now evident.

Cite this collection

Dolan, Stephen K.; Bock, Tobias; Hering, Vanessa; A. Owens, Rebecca; W. Jones, Gary; Blankenfeldt, Wulf; Doyle, Sean (2017): Supplementary material from "Structural, mechanistic and functional insight into gliotoxin bis-thiomethylation in Aspergillus fumigatus". figshare.

https://doi.org/10.6084/m9.figshare.c.3672997.v1

Retrieved: 17:34, Sep 19, 2017 (GMT)