Category: catabolism
The kynurenine pathway (KP) handles ~95% of dietary tryptophan catabolism — the dominant non-serotonin tryptophan route. Rate-limiting enzymes: tryptophan 2,3-dioxygenase (TDO, hepatic, substrate-induced) + indoleamine 2,3-dioxygenase (IDO1, induced by IFN-γ + LPS in immune + epithelial cells). TDO/IDO oxidize Trp → N-formylkynurenine → kynurenine (the branch hub). Kynurenine routes: (1) Kynurenine 3-monooxygenase (KMO) → 3-hydroxykynurenine → 3-hydroxyanthranilic acid → quinolinic acid (QUIN, NMDA agonist + neurotoxin) → niacin / NAD⁺ synthesis (cross-link [[niacin_nad_synthesis]]). (2) Kynurenine aminotransferases (KAT-I/II/III/IV) → kynurenic acid (KYNA, NMDA + α7-nAChR antagonist — neuroprotective; cognitive-decline-associated in excess). Immunometabolism: IDO1 is a dominant immune checkpoint — local Trp depletion + Kyn accumulation suppresses effector T cells + drives Treg differentiation (cross-link [[cd4_helper_th1_th2_th17_treg]]). Tumor microenvironment exploits IDO1 for immune evasion. Therapeutic landscape: IDO1 inhibitors (epacadostat — failed phase 3 melanoma; indoximod, linrodostat in trials); KP-psychiatric link (depression has elevated kynurenine + QUIN/KYNA imbalance; ketamine bypasses QUIN-NMDA; psychedelics reduce IDO activity); pyridoxine + niacin support upstream + downstream balance. Cross-links: [[serotonin_melatonin_axis]] (5-HT competing branch), [[niacin_nad_synthesis]] (downstream NAD⁺), [[cd4_helper_th1_th2_th17_treg]] (Treg induction).