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).
Organ Systems
immune-hematologic
nervous
endocrine
Pathway Steps
dietary L-tryptophan → N-formylkynurenine — via TDO (hepatic, substrate-induced) or IDO1 (immune cells, IFN-γ-induced). This is the quantitatively dominant fate of tryptophan (~95%, vs the minor serotonin branch). Hepatic TDO is substrate/cortisol-induced while immune-cell IDO1 is IFN-γ-induced — so inflammation diverts tryptophan here and depletes serotonin precursor.
N-formylkynurenine → kynurenine (the branch hub) — via formamidase (spontaneous + enzymatic deformylation). Kynurenine is the branch hub, partitioning between the neurotoxic (3-HK/quinolinic) and neuroprotective (kynurenic) arms. It crosses the blood–brain barrier, so peripheral immune/hepatic production shapes CNS kynurenine metabolism.
kynurenine + KMO → 3-hydroxykynurenine → 3-HAA — via flavin-dependent monooxygenase; rate-limiting for QUIN branch. KMO commits flux toward the quinolinic (neurotoxic) arm and is rate-limiting for it; 3-hydroxykynurenine is itself a pro-oxidant. KMO inhibition (shunting toward neuroprotective kynurenic acid) is studied in Huntington’s and neurodegeneration.
3-HAA → ACMSD → quinolinic acid (QUIN — NMDA agonist) — via → niacin / NAD⁺ synthesis (cross-link niacin_nad_synthesis). Quinolinic acid is both the precursor for de-novo NAD⁺ synthesis (cross-link niacin_nad_synthesis) and an NMDA-agonist excitotoxin. ACMSD diverts substrate toward picolinic acid, setting how much goes to NAD versus excitotoxicity.
kynurenine + KAT-I/II/III/IV → kynurenic acid (KYNA — NMDA + α7-nAChR antagonist) — via neuroprotective at low levels; cognitive impairment in excess. Kynurenine aminotransferases make kynurenic acid, an NMDA and α7-nicotinic antagonist — neuroprotective at low levels but, when elevated, implicated in the cognitive deficits of schizophrenia. The KYNA:QUIN balance is the pathway’s key functional readout.
IDO1 induction (tumor / Treg) → local Trp depletion + Kyn accumulation — via immune checkpoint: effector T-cell arrest + Treg differentiation. IDO1 induction in tumors and regulatory T cells is an immune-checkpoint mechanism: local tryptophan depletion arrests effector T cells while kynurenine (an aryl-hydrocarbon-receptor ligand) drives Treg differentiation — the rationale for IDO-inhibitor immuno-oncology.