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.
Highlights
The inducible phase II enzymes known as glutathione transferases (GSTs; E.C. 2.5.1.18) conjugate endogenous and xenobiotic toxins with electrophilic centers to glutathione (c-glucys-gly, GSH)
Polymorphisms in the Omega class GSTs have been associated with the age at onset of Alzheimer’s and Parkinson’s diseases [6], familial amyotrophic lateral sclerosis [7], and the development of acute childhood lymphoblastic leukemia [8]
Our attempt to determine the structure of hGSTO1-1 in complex with 4NPG has revealed glutathione molecule and results in oxidized glutathione (GSSG) bound in the active site and 4NPG bound at the dimer interface (Figure 2)
Summary
The inducible phase II enzymes known as glutathione transferases (GSTs; E.C. 2.5.1.18) conjugate endogenous and xenobiotic toxins with electrophilic centers to glutathione (c-glucys-gly, GSH). Several classes function as glutathione peroxidases or as reductases [1]. Among the human isozymes are the cytoplasmic alpha, zeta, theta, mu, pi, sigma and omega classes. The most recently described family in humans is omega: two isozymes have been identified (designated hGSTO1-1 and hGSTO2-2) [2,3]. The Omega class GSTs are associated with biological processes including the modulation of ryanodine receptors [4] and the activation of IL-1b [5]. Polymorphisms in the Omega class GSTs have been associated with the age at onset of Alzheimer’s and Parkinson’s diseases [6], familial amyotrophic lateral sclerosis [7], and the development of acute childhood lymphoblastic leukemia [8]
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