title: Modulation of GSTP1-1 oligomerization by electrophilic inflammatory mediators and reactive drugs.
abstract: Glutathione S transferase P1-1 plays a key role in the metabolism of inflammatory mediators and drugs, thus modulating the inflammatory response. Active GSTP1-1 is a homodimer with cysteine residues close to the active site that can undergo oligomerization in response to stress, a process that affects enzyme activity and interactions with signaling and redox-active proteins. Cyclopentenone prostaglandins (cyPG) are endogenous reactive lipid mediators that participate in the regulation of inflammation and may covalently modify proteins through Michael addition. cyPG with dienone structure, which can bind to vicinal cysteines, induce an irreversible oligomerization of GSTP1-1. Here we have characterized the oligomeric state of GSTP1-1 in Jurkat cells treated with 15-deoxy-Δ12,14-PGJ2(15d-PGJ2). 15d-PGJ2induces both reversible and irreversible GSTP1-1 oligomerization as shown by blue-native 2D electrophoresis. Interestingly, GSTP1-1 dimers were the main species detected by analytical gel filtration chromatography in control cells, whereas only oligomers, compatible with a tetrameric association state, were found in 15d-PGJ2-treated cells. cyPG-induced GSTP1-1 oligomerization also occurred in cell-free systems. Therefore, we employed this model to assess the effects of endogenous reactive species and drugs. Inflammatory mediators, such as 15d-PGJ2and Δ12-PGJ2, and drugs like chlorambucil, phenylarsine oxide or dibromobimane elicited whereas ethacrynic acid hampered GSTP1-1 oligomerization or intra-molecular cross-linking in cell-free systems, yielding GSTP1-1 species specific for each compound. These observations situate GSTP1-1 at the cross-roads of inflammation and drug action behaving as a target for both inflammatory mediators and reactive drugs, which induce or reciprocally modulate GSTP1-1 oligomerization or conformation.
authors.affiliation: Chemical and Physical Biology Department, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu, 9, 28040 Madrid, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Sánchez-Gómez
authors.forename: Carlos García
authors.initials: CG
authors.lastname: Dorado
authors.forename: Pedro
authors.initials: P
authors.lastname: Ayuso
authors.forename: Jose A G
authors.initials: JA
authors.lastname: Agúndez
authors.forename: María A
authors.initials: MA
authors.lastname: Pajares
authors.forename: Dolores
authors.initials: D
authors.lastname: Pérez-Sala
mesh_terms: D002474:Cell-Free System; D003517:Cyclopentanes / Q000494:pharmacology; D051549:Glutathione S-Transferase pi / Q000378:metabolism*; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D019169:Jurkat Cells; D050217:Metabolic Detoxication, Phase II; D058990:Molecular Targeted Therapy; D010084:Oxidation-Reduction; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D055503:Protein Multimerization / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C477819:15-deoxyprostaglandin J2; D003517:Cyclopentanes; D006841:Hydrocarbons, Aromatic; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D051549:Glutathione S-Transferase pi; C013905:cyclopentenone; D015230:Prostaglandin D2