期刊
OPEN BIOLOGY
卷 7, 期 2, 页码 -出版社
ROYAL SOC
DOI: 10.1098/rsob.160292
关键词
methyltransferase; NRPS; quantitativeproteomics; Aspergillus
资金
- Science Foundation [13/CDA/2142]
- Helmholtz Zentrum Berlin (Germany)
- European Synchrotron Radiation Facility (ESRF Grenoble, France)
- Deutsches Elektronen-Synchrotron (DESY, Hamburg, Germany)
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 angstrom), GtmA complexed to S-adenosylhomocysteine (1.33 angstrom) and GtmA complexed to S-adenosylmethionine (2.28 angstrom), providingmechanistic 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 Delta gliT:: Delta gmA 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 GtmAand functionality of ETP bis-thiomethylation as an ancestral protection strategy against dithiol compounds is now evident.
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