Physiological Role of Gamma-Glutamyl Transpeptidase: Demise of The Gamma-Glutamyl Cycle.

Gamma-glutamyl transpeptidase (GGT) is an enzyme with a plethora of names and purported functions. The enzyme has long been identified with an amino acid transport system called the gamma-glutamyl cycle which was proposed in the 1970s. The foundation of this cycle held that GGT catalyzed a transpeptidation reaction and in the process transported an extracellular amino acid into the cell as a gamma-glutamyl amino acid. However, subsequent studies showed that under physiological conditions the enzyme is a hydrolase. It cleaves the gamma-glutamyl bond of glutathione, glutathione S-conjugates and other gamma-glutamyl compounds releasing glutamate. The release of glutamate from glutathione, renders the second product of the reaction, cysteinyl-glycine, susceptible to cleavage by cell surface dipeptidases. The development of the GGT-deficient mouse showed definitively that the primary role of GGT in vivo is cysteine homeostasis, not amino acid transport. GGT also plays a role in oxidative stress, drug metabolism, and inflammation. Despite numerous studies showing that the gamma-glutamyl cycle is incorrect, it nonetheless persists in the literature, in textbooks, and currently on the GGT Wikipedia page. Confusion regarding the physiological role of GGT can lead to misinterpretation of data and blunt progress in many important areas of investigation. This review focuses on the physiological functions of GGT and summarizes the data demonstrating the gamma-glutamyl cycle does not exist.