title: The role of glutathione S-transferase GliG in gliotoxin biosynthesis in Aspergillus fumigatus.
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.
authors.affiliation: Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland.
authors.forename: Carol
authors.initials: C
authors.lastname: Davis
authors.forename: Stephen
authors.initials: S
authors.lastname: Carberry
authors.forename: Markus
authors.initials: M
authors.lastname: Schrettl
authors.forename: Ishwar
authors.initials: I
authors.lastname: Singh
authors.forename: John C
authors.initials: JC
authors.lastname: Stephens
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Barry
authors.forename: Kevin
authors.initials: K
authors.lastname: Kavanagh
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Challis
authors.forename: Dermot
authors.initials: D
authors.lastname: Brougham
authors.forename: Sean
authors.initials: S
authors.lastname: Doyle
mesh_terms: D001232:Aspergillus fumigatus / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D005912:Gliotoxin / Q000096:biosynthesis*; D005982:Glutathione Transferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism; D010641:Phenotype; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D005912:Gliotoxin; D010088:Oxidoreductases; D005982:Glutathione Transferase