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Structural insights into omega-class glutathione transferases: a snapshot of enzyme reduction and identification of a non-catalytic ligandin site

Journal Article


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Abstract


  • Glutathione transferases (GSTs) are dimeric enzymes containing one active-site per monomer. The omega-class GSTs (hGSTO1-1 and hGSTO2-2 in humans) are homodimeric and carry out a range of reactions including the glutathione-dependant reduction of a range of compounds and the reduction of S-(phenacyl)glutathiones to acetophenones. Both types of reaction result in the formation of a mixed-disulfide of the enzyme with glutathione through the catalytic cysteine (C32). Recycling of the enzyme utilizes a second glutathione molecule and results in oxidized glutathione (GSSG) release. The crystal structure of an active-site mutant (C32A) of the hGSTO1-1 isozyme in complex with GSSG provides a snapshot of the enzyme in the process of regeneration. GSSG occupies both the G (GSH-binding) and H (hydrophobic-binding) sites and causes re-arrangement of some H-site residues. In the same structure we demonstrate the existence of a novel “ligandin” binding site deep within in the dimer interface of this enzyme, containing S-(4-nitrophenacyl)glutathione, an isozyme-specific substrate for hGSTO1-1. The ligandin site, conserved in Omega class GSTs from a range of species, is hydrophobic in nature and may represent the binding location for tocopherol esters that are uncompetitive hGSTO1-1 inhibitors.

Authors


  •   Brock, Joseph (external author)
  •   Board, Philip G. (external author)
  •   Oakley, Aaron J.

Publication Date


  • 2013

Citation


  • Brock, J., Board, P. G. & Oakley, A. J. (2013). Structural insights into omega-class glutathione transferases: a snapshot of enzyme reduction and identification of a non-catalytic ligandin site. PLoS One, 8 (4), e60324.

Scopus Eid


  • 2-s2.0-84876047892

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1442&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/430

Start Page


  • e60324

Volume


  • 8

Issue


  • 4

Abstract


  • Glutathione transferases (GSTs) are dimeric enzymes containing one active-site per monomer. The omega-class GSTs (hGSTO1-1 and hGSTO2-2 in humans) are homodimeric and carry out a range of reactions including the glutathione-dependant reduction of a range of compounds and the reduction of S-(phenacyl)glutathiones to acetophenones. Both types of reaction result in the formation of a mixed-disulfide of the enzyme with glutathione through the catalytic cysteine (C32). Recycling of the enzyme utilizes a second glutathione molecule and results in oxidized glutathione (GSSG) release. The crystal structure of an active-site mutant (C32A) of the hGSTO1-1 isozyme in complex with GSSG provides a snapshot of the enzyme in the process of regeneration. GSSG occupies both the G (GSH-binding) and H (hydrophobic-binding) sites and causes re-arrangement of some H-site residues. In the same structure we demonstrate the existence of a novel “ligandin” binding site deep within in the dimer interface of this enzyme, containing S-(4-nitrophenacyl)glutathione, an isozyme-specific substrate for hGSTO1-1. The ligandin site, conserved in Omega class GSTs from a range of species, is hydrophobic in nature and may represent the binding location for tocopherol esters that are uncompetitive hGSTO1-1 inhibitors.

Authors


  •   Brock, Joseph (external author)
  •   Board, Philip G. (external author)
  •   Oakley, Aaron J.

Publication Date


  • 2013

Citation


  • Brock, J., Board, P. G. & Oakley, A. J. (2013). Structural insights into omega-class glutathione transferases: a snapshot of enzyme reduction and identification of a non-catalytic ligandin site. PLoS One, 8 (4), e60324.

Scopus Eid


  • 2-s2.0-84876047892

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1442&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/430

Start Page


  • e60324

Volume


  • 8

Issue


  • 4