Glutamate–cysteine ligase (GCL) EC 6.3.2.2), previously known as γ-glutamylcysteine synthetase (GCS), is the first enzyme of the cellular glutathione (GSH) biosynthetic pathway that catalyzes the chemical reaction: L-glutamate + L-cysteine + ATP
Nearly every eukaryotic cell, from plants to yeast to humans, expresses a form of the GCL protein for the purpose of synthesizing GSH.
[2][3] This typically involves impaired function leading to decreased GSH biosynthesis, reduced cellular antioxidant capacity, and the induction of oxidative stress.
However, in cancer, GCL expression and activity is enhanced, which serves to both support the high level of cell proliferation and confer resistance to many chemotherapeutic agents.
[6] This peptide bond is resistant to cleavage by cellular peptidases and requires a specialized enzyme, gamma-glutamyl transpeptidase (γGT), to metabolize γ-GC and GSH into its constituent amino acids.
[22] Mice lacking the modulatory subunit demonstrate no obvious phenotype, but exhibit marked decrease in GSH and increased sensitivity to toxic insults.
[28] Studies also shown that restricting GCL activity to the cytosol or glutathione biosynthesis to the plastids is sufficient for normal plant development and stress tolerance.