Category: biosynthesis
Glutathione (GSH; γ-glutamyl-cysteinyl-glycine) is the major intracellular antioxidant + xenobiotic conjugator. Synthesis: glutamate + cysteine → γ-glutamylcysteine via γ-glutamylcysteine synthetase (γ-GCS) — RATE-LIMITING, inhibited by GSH (negative feedback). γ-GC + glycine → GSH (GSS). Redox cycle: GSH + ROS → GSSG (oxidized) via glutathione peroxidase (selenium cofactor); GSSG → GSH via glutathione reductase (NADPH from PPP). Acetaminophen toxicity: NAPQI (CYP2E1 metabolite of APAP, normally <5% of dose) depletes hepatic GSH; once GSH falls below ~30% of baseline, NAPQI covalently binds liver proteins → centrilobular necrosis. N-ACETYLCYSTEINE rescues by replenishing cysteine for GSH synthesis (most effective <8h post-ingestion).