The Many Faces of Glutathione Transferase Pi

Abstract

Glutathione transferase Pi (GST-pi, GSTP) is known to strongly affect human susceptibility to several cancers, asthma and neurodegenerative disorders. As with other glutathione transferases, it catalyses the addition of reduced glutathione to electrophilic species, and it is important in metabolite detoxification. It also was shown to bind proteins and compounds containing iron and nitric oxide. Some of these interactions have developed in the course of evolution into regulatory pathways that back up the GST's most ancient catalytic functions and provide precise and diverse responses to chemical and redox stresses. An aim of this review is to summarise recent knowledge on GSTP's complementary functions in crosstalking pathways of conventional glutathione transfer, nitric oxide and lipid metabolism and ASK1-dependent stress response. This review will describe how these complex interactions affect regulation of cell respiration, biosynthesis of lung surfactant, organism's immunity and circadian rhythms. Integration of the data leads to a new interpretation of the role of GSTP in normal human physiology, pathology and an organism's susceptibility to diseases.

Glutathione-S-Transferases in Development, Progression and Therapy of Colorectal Cancer

“…Some of the GSTs can serve as nonenzymatic binding proteins (known as ligandins) interacting with various lipophilic compounds including steroid and thyroid hormones (Litwack et al, 1971;Ishigaki et al, 1989;Cho et al, 2001;Vasieva, 2011). Moreover, GST isoenzymes can play a regulatory role in cellular signaling by forming protein:protein interactions with key signaling tyrosine kinases, involved in controlling stress response, apoptosis, inflammation, cellular differentiation and proliferation (Adler et al, 1999;Cho et al, 2001;Wang et al, 2001;Townsend &Tew, 2003;Townsend et al, 2005;McIlwain et al, 2006;Laborde, 2010;Vasieva, 2011). There is strong evidence that GST-pi can bind by protein:protein interaction, sequester and inhibit c-Jun N-terminal kinase (JNK)/stress-activated protein kinases (SAPKs).…”

“…JNK is a MAP kinase that phosphorylates c-Jun, a component of the activator protein-1 (AP-1) transcriptional factor, resulting in the induction of AP-1-dependent target genes which play role in cell survival and apoptosis. Thus JNK is implicated in pro-apoptotic/survival signaling pathways and may be required for induced cytotoxicity of a variety of antitumor drugs (Adler et al, 1999;Wang et al, 2001;Townsend &Tew, 2003;Townsend et al, 2005;McIlwain et al, 2006;Laborde, 2010;Vasieva, 2011). Recently, GST-pi was shown to affect the apoptosis pathways also by physical association with TNF receptor associated factor 2 (TRAF2), an adaptor protein which mediates the signal transduction of different receptors and is required for the activation of ASK1 (apoptosis signal-regulating kinase 1) (Wu et al, 2006;Laborde, 2010;Sau et al, 2010; www.intechopen.com Vasieva, 2011).…”

“…Thus JNK is implicated in pro-apoptotic/survival signaling pathways and may be required for induced cytotoxicity of a variety of antitumor drugs (Adler et al, 1999;Wang et al, 2001;Townsend &Tew, 2003;Townsend et al, 2005;McIlwain et al, 2006;Laborde, 2010;Vasieva, 2011). Recently, GST-pi was shown to affect the apoptosis pathways also by physical association with TNF receptor associated factor 2 (TRAF2), an adaptor protein which mediates the signal transduction of different receptors and is required for the activation of ASK1 (apoptosis signal-regulating kinase 1) (Wu et al, 2006;Laborde, 2010;Sau et al, 2010; www.intechopen.com Vasieva, 2011). ASK1 is a MAP kinase kinase kinase (MAP3 kinase, MAPKKK) that can phosphorylate MKK4/7 and MKK3/6 (MAP kinase kinases, MAP2Ks, MAPKK) which are involved in stress-induced activation of JNK-and p38 signaling pathways, respectively (Dorion et al, 2002;Wu et al, 2006;Sau et al, 2010).…”

“…Another binding partner of GST-pi is the antioxidant enzyme 1-cys peroxiredoxin (1-cysPrx, Prx VI), which is a member of the peroxiredoxin superfamily and is able to protect cells from membrane peroxidation via GSH-dependent peroxidase activity on phospholipid hydroperoxides. The process of heterodimerization of 1-cysPrx with GST-pi leads to activation involving also the S-glutathionylation of 1-cysPrx (Manevich et al, 2004;Vasieva, 2011). GST-pi has also been found to function in the S-glutathionylation of oxidized cysteine residues of several target proteins following oxidative and nitrosative stress thus playing a direct role in the control of posttranslational S-glutathionylation reactions (McIlwain et al, 2006;Townsend et al, 2006;Townsend et al, 2009;Tew et al, 2011).…”

“…Since a number of proteins that are S-glutathionylated are involved in growth regulatory pathways, the overexpression of GST-pi in cancers may account for the impaired balance between cell death, proliferation and differentiation and could contribute to tumor development, progression and treatment response (Townsend et al, 2009;Tew et al, 2011). GST-pi was also shown to bind proteins and compounds containing iron and nitric oxide and thus may influence the NO metabolism and NO signaling (Vasieva, 2011). It has been shown that the natural low molecular mass NO carriers, dinitrosyl-iron complexes (DNIC) and S-nitrosoglutathion (GSNO) bind with high affinity to one active site of the dimeric GST-pi enzyme, while the enzyme maintains its detoxification activity (Lo Bello et al, 2001;Townsend et al, 2006;Vasieva, 2011).…”