GCLC

GCLC stands for glutamate-cysteine ligase catalytic subunit, the catalytic component of gamma-glutamylcysteine ligase (GCL). GCL is the first and rate-limiting step in the biosynthesis of the antioxidant glutathione (GSH). The enzyme catalyzes the ATP-dependent condensation of glutamate and cysteine to form gamma-glutamylcysteine, which is subsequently coupled with glycine to produce GSH.

GCL functions as a heterodimer composed of the catalytic subunit GCLC and the modifier subunit GCLM. GCLC provides the catalytic activity, while GCLM modulates the enzyme’s kinetic properties and its feedback inhibition by glutathione, allowing adjustment of GSH synthesis under varying cellular needs.

Expression and activity of GCLC are regulated by the cellular redox state. Oxidative stress and electrophiles activate signaling pathways, notably the Nrf2-ARE axis, leading to increased transcription of GCLC. Post-translational modifications and substrate availability also influence the enzyme’s activity. The level of GCLC, together with GCLM, determines the capacity of cells to synthesize glutathione.

The GCLC gene is located on chromosome 6p12 in humans and can generate multiple transcript variants through alternative splicing, contributing to tissue- and context-specific expression patterns.

Clinical and research relevance of GCLC centers on its role in maintaining cellular redox balance. Impaired GCLC function or regulation can reduce glutathione synthesis and increase vulnerability to oxidative stress. Conversely, elevated GCLC activity or glutathione levels can support the survival of some cancer cells, making the GCL system a potential target for therapeutic intervention.