Targeting gamma-glutamyl transpeptidase: A pleiotropic enzyme involved in glutathione metabolism and in the control of redox homeostasis

Abstract

Gamma-glutamyl transpeptidase (GGT) is an enzyme located on the outer membrane of the cells where it regulates the metabolism of glutathione (GSH), the most abundant intracellular antioxidant thiol. GGT plays a key role in the control of redox homeostasis, by hydrolyzing extracellular GSH and providing the cell with the recovery of cysteine, which is necessary for de novo intracellular GSH and protein biosynthesis. Therefore, the upregulation of GGT confers to the cell greater resistance to oxidative stress and the advantage of growing fast. Indeed, GGT is upregulated in inflammatory conditions and in the progression of various human tumors and it is involved in many physiological disorders related to oxidative stress, such as cardiovascular disease and diabetes. Currently, increased GGT expression is considered a marker of liver damage, cancer, and low-grade chronic inflammation. This review addresses the current knowledge on the structure-function relationship of GGT, focusing on human GGT, and provides information on the pleiotropic biological role and relevance of the enzyme as a target of drugs aimed at alleviating oxidative stress-related diseases. The development of new GGT inhibitors is critically discussed, as are the advantages and disadvantages of their potential use in clinics. Considering its pleiotropic activities and evolved functions, GGT is a potential "moonlighting protein".

Keywords: GGT inhibitors; Gamma-glutamyl transpeptidase; Glutathione; Oxidative stress; Redox homeostasis.