Category: signaling
Distinct from glutathione_metabolism (synthesis arm: γ-GCS → γ-GC + glycine → GSH) and transsulfuration_cysteine_glutathione (precursor arm: homocysteine → cysteine → GSH). This pathway covers the **redox cycling** arm — how reduced GSH is consumed to neutralize peroxides and how the oxidized GSSG is regenerated to maintain antioxidant reserve. Step 1: glutathione peroxidase (GPx, selenoenzyme — selenocysteine in the active site) reduces H₂O₂ → H₂O + GSSG. Step 2: glutathione peroxidase 4 (GPx4) reduces phospholipid hydroperoxides → the canonical defense against lipid peroxidation; GPx4 deficiency drives ferroptosis. Step 3: glutathione reductase (GR, FAD-flavoenzyme) reduces GSSG → 2 GSH consuming NADPH. Step 4: NADPH is supplied by the pentose phosphate pathway (G6PD, the rate-limiting step — G6PD-deficient patients are susceptible to hemolytic crisis with oxidative stressors like sulfa drugs / fava beans because they cannot regenerate GSH). Step 5: peroxiredoxins (Prx1-6, abundant thiol-peroxidases) operate in parallel + crosstalk with GSH redox. Step 6: GSH/GSSG ratio (normally ~100:1 in cytosol, ~10:1 in mitochondria) is a master redox-state indicator — falling ratio triggers Nrf2 activation, sirtuin modulation, and apoptotic priming. Therapeutic relevance: selenium deficiency → diminished GPx capacity; vitamin E (chain-breaking lipid antioxidant) cooperates with GPx4 to prevent peroxide propagation; astaxanthin + carotenoids extend the GSH/GPx antioxidant chain. Cross-links: [[glutathione_metabolism]], [[transsulfuration_cysteine_glutathione]], [[ros_oxidative_stress]], [[nrf2_keap1_antioxidant_response]] (GSH/GSSG redox state is the canonical input to Keap1 cysteine sensing), [[pentose_phosphate_pathway]] (NADPH supply).