Pleiotropic functions of glutathione S-transferase P

Abstract

Glutathione S-transferase P (GSTP) is one member of the GST superfamily that is prevalently expressed in mammals. Known to possess catalytic activity through deprotonating glutathione allowing formation of thioether bonds with electrophilic substrates, more recent discoveries have broadened our understanding of the biological roles of this protein. In addition to catalytic detoxification, other properties so far ascribed to GSTP include chaperone functions, regulation of nitric oxide pathways, regulation of a variety of kinase signaling pathways, and participation in the forward reaction of protein S-glutathionylation. The expression of GSTP has been linked with cancer and other human pathologies and more recently even with drug addiction. With respect to human health, polymorphic variants of GSTP may determine individual susceptibility to oxidative stress and/or be critical in the design and development of drugs that have used redox pathways as a discovery platform.

Keywords: Allelic variants; Cysteine; Glutathione; Glutathione S-transferase; Kinase signaling; Nitric oxide; Nitrosylation; Peroxiredoxins; Protein–protein interactions; Sulfur.

Figure 4.1

Representative example of phase II detoxification of an electrophilic compound via GSTP, with ATP-binding cassette transporter participation in efflux.

Figure 4.2

Some examples of how GSTP has been shown to participate in regulating various kinase signaling pathways. GSTP is a negative regulator in TNFα-induced MAPK signaling. It interacts physically with TRAF2, which blocks the interaction of TRAF2 and ASK1, attenuates ASK1 autophosphorylation, and in turn suppresses TNFα–ASK1–JNK/p38 signaling pathways. GSTP is also able to directly sequester JNK in a complex, thus preventing it from acting on downstream targets, c-Jun and ATF2. In contrast, GSTP can amplify Fas-induced MAPK signaling. Stimulation of Fas ligand increased the interaction of GSTP with Fas and ERp57 in the ER leading to Fas S-glutathionylation and subsequent mobilization from ER to cytosol, resulting in enhanced Fas–ASK1–JNK/p38 signaling pathways.

Figure 4.3

Representation from the literature of proteins clustered into functional groups that are known to be susceptible to S-glutathionylation.

Figure 4.4

S-glutathionylation cycle of redox sensors. PTP1B is a representative protein with a low-pKa residue (redox sensor) that is a target for oxidative or nitrosative stress. Cysteine residues within redox sensors can be oxidized to form protein sulfenic (P-OH) and sulfinic (P-OOH) acids. Protein S-glutathionylation (P-SSG) reactions can be spontaneous or are mediated by GGT, Grx, or GSTP. P-SSG proteins have a wide variety of functions in cellular physiology/pathology.

Figure 4.5

Catalytic cycle of Prdx6 activation by GSTP1. Reduction of phospholipid hydroperoxide (PLPCOOH) or H₂O₂ by Prdx6 results in oxidation of its catalytic Cys47 to sulfenic acid (shown in red). This oxidized monomer of Prdx6 forms a heterodimer with thiolate anion-bearing (shown in blue) GSTP. The spontaneous reaction of the thiolate anion with the catalytic Cys47 sulfenate of Prdx6 results in the S-glutathionylation of the latter (shown in box; the critical step of Prdx6 activation). Alignment of the S-glutathionylated catalytic Cys47 of Prdx6 with the catalytic Cys47 of GSTP results in the formation of a disulfide-based heterodimer. GSH access to the disulfide bond results in catalytic cysteine reduction/activation (shown in green) and heterodimer dissociation.

Figure 4.6

Ribbon depiction of the DNGIC/GSTP1-1 complex. The close-up view of the active site of the covalent DNGIC (as obtained after removal of the excess GSH) is shown. The model shows that (i) one of the GSH ligands of DNDGIC can dock into the G-site and adopt the canonical extended conformation seen in crystal structures of GST–GSH complexes, (ii) Tyr7 is close enough to displace the other GSH ligand to generate a stable enzyme-inhibitor complex, and (iii) the NO moieties of the complex form van der Waal’s interactions with Ile104 and Tyr108. In addition, there are possible polar interactions with Tyr108 and the main chain nitrogen of Gly205. The iron atom is depicted as an orange sphere, oxygen atoms are colored red, nitrogen atoms are blue, sulfur atoms are yellow, and carbon atoms are green. This figure was drawn using MOLSCRIPT. Reproduced from Lo Bello et al. (2001) with permission.