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

Caroll Davis; S Carberry; M Schrettl; I Singh; J. C. Stephens; Sarah M. Barry; K. Kavanagh; Gregory L. Challis; D. Brougham; Sean Doyle

doi:10.1016/j.chembiol.2010.12.022

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

Caroll Davis, S Carberry, M Schrettl, I Singh, J. C. Stephens, Sarah M. Barry, K. Kavanagh, Gregory L. Challis, D. Brougham, Sean Doyle

Chemistry

University of Warwick

Research output: Contribution to journal › Article › peer-review

74 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 language	English
Article number	N/A
Pages (from-to)	542-552
Number of pages	11
Journal	Chemistry and Biology
Volume	18
Issue number	4
DOIs	https://doi.org/10.1016/j.chembiol.2010.12.022
Publication status	Published - 22 Apr 2011

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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.",

author = "Caroll Davis and S Carberry and M Schrettl and I Singh and Stephens, {J. C.} and Barry, {Sarah M.} and K. Kavanagh and Challis, {Gregory L.} and D. Brougham and Sean Doyle",

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AU - Davis, Caroll

AU - Carberry, S

AU - Schrettl, M

AU - Singh, I

AU - Stephens, J. C.

AU - Barry, Sarah M.

AU - Kavanagh, K.

AU - Challis, Gregory L.

AU - Brougham, D.

AU - Doyle, Sean

PY - 2011/4/22

Y1 - 2011/4/22

N2 - 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.

AB - 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.

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DO - 10.1016/j.chembiol.2010.12.022

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JO - Chemistry and Biology

JF - Chemistry and Biology

IS - 4

M1 - N/A

ER -

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

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