The Relationship of Glutathione-S-Transferase and Multi-Drug Resistance-Related Protein 1 in Nitric Oxide (NO) Transport and Storage

Abstract

Nitric oxide is a diatomic gas that has traditionally been viewed, particularly in the context of chemical fields, as a toxic, pungent gas that is the product of ammonia oxidation. However, nitric oxide has been associated with many biological roles including cell signaling, macrophage cytotoxicity, and vasodilation. More recently, a model for nitric oxide trafficking has been proposed where nitric oxide is regulated in the form of dinitrosyl-dithiol-iron-complexes, which are much less toxic and have a significantly greater half-life than free nitric oxide. Our laboratory has previously examined this hypothesis in tumor cells and has demonstrated that dinitrosyl-dithiol-iron-complexes are transported and stored by multi-drug resistance-related protein 1 and glutathione-S-transferase P1. A crystal structure of a dinitrosyl-dithiol-iron complex with glutathione-S-transferase P1 has been solved that demonstrates that a tyrosine residue in glutathione-S-transferase P1 is responsible for binding dinitrosyl-dithiol-iron-complexes. Considering the roles of nitric oxide in vasodilation and many other processes, a physiological model of nitric oxide transport and storage would be valuable in understanding nitric oxide physiology and pathophysiology.

S-Denitrosylation: A Crosstalk between Glutathione and Redoxin Systems

“…This tripeptide is a pivotal Non-Protein Thiol (NPSH) present in 5–10 mM concentrations physiologically and is synthesized in the cytosol from glutamate through a feedback mechanism [ 19 ]. Several pathways have come to light in recent days related to the biosynthesis of ϒ-glutamylcysteine from the conjugation of glutamate and cysteine; the most common being the de novo GSH synthesis through the ϒ-glutamyl cycle, involving ϒ-glutamyl transpeptidase, peptidase, and ϒ-glutamylcysteine synthetase to catalyze the biosynthesis.…”