![]() ![]() Resistance genes are required to allow a toxin producer to grow in the presence of its own metabolic weaponry, and ETPs are no exception to this rule. gtmA is encoded outside the cluster and is on chromosome 2. fumigatus, the gli-cluster that encodes gliotoxin biosynthesis consists of 13 genes (in colour and labelled with their last letter) and is located on chromosome 6. Conversion of gliotoxin between the reduced (dithiol gliotoxin), oxidized (gliotoxin) and bisthiomethyl forms. The stereochemically complex core of ETPs, coupled with their potent biological activities, make these compounds an attractive target for drug leads. Although the mechanism of action for the cytotoxicity of gliotoxin has not been fully elucidated, two primary activities have been described: the generation of reactive oxygen species (ROS) through oxidation of the disulfide bridge and mixed disulfide formation. As with other ETPs, gliotoxin is produced through a sequential series of enzymatic steps which are organized into a coordinated biosynthetic gene cluster ( figure 1). Gliotoxin, produced by the opportunistic fungus Aspergillus fumigatus, is the prototypic member of this large family. ![]() Įpipolythiodioxopiperazine (ETP) alkaloids are toxic natural products characterized by a unique bridged disulfide or polysulfide dioxopiperazine ring. Production of these natural products requires a carefully orchestrated system to balance biosynthesis while avoiding self-harm from endogenous accumulation of toxic natural product precursors. Although many of these compounds are known as clinically important drugs or industrial chemicals, several natural products are potent toxins that pose substantial threats to human food supplies and health. 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.Īscomycetes constitute the largest phylum of the fungal kingdom and produce a copious array of natural products. 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. ![]() Indeed, quantitative proteomic analysis of Δ gliT::Δ gtmA reveals an uncontrolled over-activation of the gli-cluster upon gliotoxin exposure. 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. We further reveal that simultaneous elimination of the ability of A. 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. Self-resistance against gliotoxin is effected by the gliotoxin oxidase GliT, and attenuation of gliotoxin biosynthesis is catalysed by gliotoxin S-methyltransferase GtmA. 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. ![]()
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