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

2.50
Hdl Handle:
http://hdl.handle.net/10033/621107
Title:
Structural, mechanistic and functional insight into gliotoxin bis-thiomethylation in Aspergillus fumigatus.
Authors:
Dolan, Stephen K; Bock, Tobias; Hering, Vanessa; Owens, Rebecca A; Jones, Gary W; Blankenfeldt, Wulf ( 0000-0001-9886-9668 ) ; Doyle, Sean
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.
Affiliation:
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Citation:
Structural, mechanistic and functional insight into gliotoxin bis-thiomethylation in Aspergillus fumigatus. 2017, 7 (2) Open Biol
Journal:
Open biology
Issue Date:
Feb-2017
URI:
http://hdl.handle.net/10033/621107
DOI:
10.1098/rsob.160292
PubMed ID:
28179499
Type:
Article
Language:
en
ISSN:
2046-2441
Appears in Collections:
publications of the scientific administration (GFW); Publications of the Dept. Structure and Functions of Proteins(SFPR)

Full metadata record

DC FieldValue Language
dc.contributor.authorDolan, Stephen Ken
dc.contributor.authorBock, Tobiasen
dc.contributor.authorHering, Vanessaen
dc.contributor.authorOwens, Rebecca Aen
dc.contributor.authorJones, Gary Wen
dc.contributor.authorBlankenfeldt, Wulfen
dc.contributor.authorDoyle, Seanen
dc.date.accessioned2017-09-13T13:49:00Z-
dc.date.available2017-09-13T13:49:00Z-
dc.date.issued2017-02-
dc.identifier.citationStructural, mechanistic and functional insight into gliotoxin bis-thiomethylation in Aspergillus fumigatus. 2017, 7 (2) Open Biolen
dc.identifier.issn2046-2441-
dc.identifier.pmid28179499-
dc.identifier.doi10.1098/rsob.160292-
dc.identifier.urihttp://hdl.handle.net/10033/621107-
dc.description.abstractGliotoxin 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.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleStructural, mechanistic and functional insight into gliotoxin bis-thiomethylation in Aspergillus fumigatus.en
dc.typeArticleen
dc.contributor.departmentHelmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalOpen biologyen

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