Gamma-glutamyltransferases: exploring the complexity of a multi-functional family of enzymes.

Gamma-glutamyltransferase (γ-GT) has long been known as a key enzyme involved in the glutathione (GSH) metabolism. The wide distribution of γ-GT expression in tissues supports its involvement in distinct processes, such as the recovery of cysteine through GSH catabolism and the metabolism of different GSH conjugates, including major inflammatory mediators leukotriene C4 and S-nitroso-glutathione and GSH-xenobiotics adducts formed by the action of glutathione-S-transferases. Most published studies have focused on γ-GT as a member in the cell antioxidant, defensive systems. Conversely, it has been documented that γ-GT may promote pro-oxidant reactions as well, with potential cell regulatory effects ranging from cell proliferation/apoptosis to drug resistance to genomic instability. From a clinical point of view, γ-GT plasma levels are a sensitive index of hepato-biliary disease and alcohol abuse. Nevertheless, during the last decade a series of large-scale, prospective studies have shown that plasma γ-GT values above the median – albeit within the reference range – are independent predictors of cardiovascular mortality, stroke, metabolic syndrome and diabetes. This appears to confirm the involvement of γ-GT in mechanisms of flogosis and hepatocellular damage, which have a role also in cardiovascular diseases and diabetes, and it is not surprising that a better understanding of γ-GT properties matches with the quest of novel γ-GT inhibitors and drugs selectively targeted on this enzyme. Insights into γ-GT structure clearly are of great interest for the development of new therapies for γ-GT-associated diseases. Despite its clinical and physiopathological importance, a full characterization of human γ-GT is still lacking, as regard both its structure and its association with circulating macromolecular complexes. The structural characterization of human γ-GT1 (hGT1) protein has been hampered by its heavily glycosylated structure and by its association with membranes. Indeed, most of the knowledge regarding γ-GT structure comes from investigations in bacteria. In their book “Gamma-Glutamyl Transpeptidases: Structure and Function” (Castellano and Merlino, 2013) the Authors provide an extensive coverage of the state-of-art knowledge on all aspects of protein structure (e.g. the autoprocessing mechanism, substrate binding sites) and enzyme reaction mechanisms. The book also provides a succinct overview of γ-GT gene family, as well as of its role in human pathology with particular regard to cancer. The latter however is a less interesting section, as the same