Dolan, Stephen K. and Owens, Rebecca A. and O'Keefe, Grainne and Hammel, Stephen and Fitzpatrick, David A. and Jones, Gary W. and Doyle, Sean (2014) Regulation of Nonribosomal Peptide Synthesis: bis-Thiomethylation Attenuates Gliotoxin Biosynthesis in Aspergillus fumigatus. Chemistry and Biology, 21 (8). pp. 999-2012. ISSN 1074-5521

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Abstract

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 postbiosynthetic regulation of nonribosomal peptide synthesis appears to be quite unusual.

Item Type:	Article
Keywords:	Nonribosomal Peptide Synthesis; bis-Thiomethylation; Gliotoxin Biosynthesis; Aspergillus fumigatus;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	7394
Identification Number:	https://doi.org/10.1016/j.chembiol.2014.07.006
Depositing User:	Dr. Sean Doyle
Date Deposited:	26 Aug 2016 14:46
Journal or Publication Title:	Chemistry and Biology
Publisher:	Elsevier
Refereed:	Yes
Funders:	Science Foundation Ireland (SFI), 3U Partnership, Irish Research Council, Higher Education Authority (HEA)
URI:	http://www.sciencedirect.com
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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