Glutamate--cysteine ligase (GCL)

Glutamate--cysteine ligase (GCL) is the enzyme catalyzing the first and rate-limiting step in glutathione (GSH) biosynthesis: the ATP-dependent condensation of L-glutamate and L-cysteine to form gamma-glutamylcysteine[1][2][3][6]. GCL is a heterodimeric enzyme comprising a catalytic subunit (GCLC) and a modifier subunit (GCLM); the catalytic subunit performs all enzymatic activity, while the modifier subunit increases efficiency and affects regulation[1][3][4]. GCL activity regulates cellular glutathione levels, crucial for antioxidant defense, detoxification, and cellular redox homeostasis. Altered GCL activity is implicated in diseases such as cancer, neurodegeneration, inflammation, and hemolytic anemia. Inhibition of GCL (e.g., by buthionine sulfoximine) is used experimentally to deplete glutathione, increasing sensitivity to oxidative stress and some chemotherapeutic agents[3][2][4][6].

Other names

gamma-glutamylcysteine synthetasegamma-glutamylcysteine ligaseγ-glutamylcysteine synthetaseγ-glutamylcysteine ligaseGCLC (catalytic subunit)GCLM (modifier subunit)

Inhibition of GCL reduces glutathione synthesis, increasing cellular susceptibility to oxidative stress and chemotherapeutic drugs[3].