Peer-Reviewed Journal Details
Mandatory Fields
Dolan, SK;Owens, RA;O'Keeffe, G;Hammel, S;Fitzpatrick, DA;Jones, GW;Doyle, S
2014
August
Chemistry and Biology
Regulation of Nonribosomal Peptide Synthesis: bis-Thiomethylation Attenuates Gliotoxin Biosynthesis in Aspergillus fumigatus
Published
42 ()
Optional Fields
MARINE-DERIVED FUNGUS STREPTOMYCES-CLAVULIGERUS INVASIVE ASPERGILLOSIS SULFHYDRYL COMPOUNDS S-METHYLTRANSFERASE GENE-CLUSTER PROTEIN METHYLATION TRANSFERASE IDENTIFICATION
21
999
1012
Gliotoxin is a redox-active nonribosomal peptide produced by Aspergillus fumigatus. Like many other disulfide-containing epipolythiodioxopiperazines, a bis-thiomethylated form is also produced. In the case of gliotoxin, bisdethiobis(methylthio) gliotoxin (BmGT) is formed for unknown reasons by a cryptic enzyme. Here, we identify the S-adenosylmethionine-dependent gliotoxin bis-thiomethyltransferase (GtmA), which converts dithiogliotoxin to BmGT. This activity, which is induced by exogenous gliotoxin, is only detectable in protein lysates of A. fumigatus deficient in the gliotoxin oxidoreductase, gliT. Thus, GtmA is capable of substrate bis-thiomethylation. Deletion of gtmA completely abrogates BmGT formation and we now propose that the purpose of BmGT formation is primarily to attenuate gliotoxin biosynthesis. Phylogenetic analysis reveals 124 GtmA homologs within the Ascomycota phylum. GtmA is encoded outside the gliotoxin biosynthetic cluster and primarily serves to negatively regulate gliotoxin biosynthesis. This mechanism of postbio-synthetic regulation of nonribosomal peptide synthesis appears to be quite unusual.
CAMBRIDGE
1074-5521
10.1016/j.chembiol.2014.07.006
Grant Details