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Crystal structure of GtmA in complex with SAH
Structural highlights
FunctionTMTA_ASPFU S-methyltransferase that catalyzes the irreversible conversion of the secondary metabolite gliotoxin to bis(methylthio)gliotoxin (BmGT). Gliotoxin, a member of the epipolythiodioxopiperazine (ETP) class of toxins, is characterized by a disulfide bridged cyclic dipeptide. Its thiol groups are essential for bioactivity, as they conjugate to sulfur-containing proteins, disturb the intracellular redox equilibrium, and generate reactive oxygen species by cycling between reduced and oxidized states. The enzyme prevents self-intoxication of the fungus by irreversible conversion of the toxic gliotoxin to a biologically inactive bis-thiomethylated derivative. Appears to negatively regulate gliotoxin biosynthesis.[1] [2] Publication Abstract from PubMedGliotoxin 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 A), GtmA complexed to S-adenosylhomocysteine (1.33 A) and GtmA complexed to S-adenosylmethionine (2.28 A), 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 DeltagliT::DeltagtmA 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. Structural, mechanistic and functional insight into gliotoxin bis-thiomethylation in Aspergillus fumigatus.,Dolan SK, Bock T, Hering V, Owens RA, Jones GW, Blankenfeldt W, Doyle S Open Biol. 2017 Feb;7(2). pii: 160292. doi: 10.1098/rsob.160292. PMID:28179499[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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