The role of glutathione S-transferase GliG in gliotoxin biosynthesis in Aspergillus fumigatus

Carol Davis, Stephen Carberry, Markus Schrettl, Ishwar Singh, John C. Stephens, Sarah M. Barry, Kevin Kavanagh, Gregory L. Challis, Dermot Brougham, Sean Doyle

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55 Citations (Scopus)

Abstract

Gliotoxin, a redox-active metabolite, is produced by the opportunistic fungal pathogen Aspergillus fumigatus, and its biosynthesis is directed by the gli gene cluster. Knowledge of the biosynthetic pathway to gliotoxin, which contains a disulfide bridge of unknown origin, is limited, although L-Phe and L-Ser are known biosynthetic precursors. Deletion of gliG from the gli cluster, herein functionally confirmed as a glutathione S-transferase, results in abrogation of gliotoxin biosynthesis and accumulation of 6-benzyl-6-hydroxy-1- methoxy-3-methylenepiperazine-2,5-dione. This putative shunt metabolite from the gliotoxin biosynthetic pathway contains an intriguing hydroxyl group at C-6, consistent with a gliotoxin biosynthetic pathway involving thiolation via addition of the glutathione thiol group to a reactive acyl imine intermediate. Complementation of gliG restored gliotoxin production and, unlike gliT, gliG was found not to be involved in fungal self-protection against gliotoxin.

Original languageEnglish
Pages (from-to)542-552
Number of pages11
JournalChemistry and Biology
Volume18
Issue number4
DOIs
Publication statusPublished - 22 Apr 2011
Externally publishedYes

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