The good Samaritan glutathione-S-transferase P1: An evolving relationship in nitric oxide metabolism mediated by the direct interactions between multiple effector molecules

Abstract

Glutathione-S-transferases (GSTs) are phase II detoxification isozymes that conjugate glutathione (GSH) to xenobiotics and also suppress redox stress. It was suggested that GSTs have evolved not to enhance their GSH affinity, but to better interact with and metabolize cytotoxic nitric oxide (NO). The interactions between NO and GSTs involve their ability to bind and store NO as dinitrosyl-dithiol iron complexes (DNICs) within cells. Additionally, the association of GSTP1 with inducible nitric oxide synthase (iNOS) results in its inhibition. The function of NO in vasodilation together with studies associating GSTM1 or GSTT1 null genotypes with preeclampsia, additionally suggests an intriguing connection between NO and GSTs. Furthermore, suppression of c-Jun N-terminal kinase (JNK) activity occurs upon increased levels of GSTP1 or NO that decreases transcription of JNK target genes such as c-Jun and c-Fos, which inhibit apoptosis. This latter effect is mediated by the direct association of GSTs with MAPK proteins. GSTP1 can also inhibit nuclear factor kappa B (NF-κB) signaling through its interactions with IKKβ and Iκα, resulting in decreased iNOS expression and the stimulation of apoptosis. It can be suggested that the inhibitory activity of GSTP1 within the JNK and NF-κB pathways may be involved in crosstalk between survival and apoptosis pathways and modulating NO-mediated ROS generation. These studies highlight an innovative role of GSTs in NO metabolism through their interaction with multiple effector proteins, with GSTP1 functioning as a "good Samaritan" within each pathway to promote favorable cellular conditions and NO levels.

Keywords: Dinitrosyl dithiol iron complexes; Glutathione S-transferase; Inducible nitric oxide synthase; Jun N-terminal kinase; NF-κB; Nitric oxide.