Glutamate-cysteine ligase (GCL) (GCL)

Glutamate-cysteine ligase (GCL) is the rate-limiting enzyme in the biosynthesis of glutathione (GSH), the primary endogenous antioxidant responsible for neutralizing reactive oxygen species (ROS) [UniProt P48506]. The enzyme exists as a heterodimer consisting of a catalytic subunit (GCLC) and a regulatory or modifier subunit (GCLM) [PubMed: 11435107]. By controlling the production of GSH, GCL directly regulates the cellular redox state and protects cells from oxidative damage, ferroptosis, and toxic insults [NIH NCBI Gene: 2729]. In oncology, GCL is often overexpressed, providing cancer cells with a survival advantage and resistance to ROS-generating therapies; thus, GCL inhibitors like buthionine sulfoximine are used to sensitize tumors [PubMed: 23603487]. In contrast, GCL deficiency or downregulation is linked to neurodegenerative conditions and chronic inflammation, where therapeutic strategies aim to induce GCL expression to mitigate oxidative stress [PubMed: 15955451]. The target name provided combines the enzyme with its primary physiological context (ROS management), reflecting its central role in antioxidant defense systems.

Other names

Gamma-glutamylcysteine synthetaseGCSGlutamate-cysteine ligase catalytic subunitGlutamate-cysteine ligase modifier subunit

Inhibition of the enzyme's catalytic activity to deplete intracellular glutathione levels, thereby increasing sensitivity to oxidative stress, or induction of enzyme expression via the Nrf2 pathway to enhance antioxidant capacity.