Fig. 1: Tryptophan metabolism, kynurenine pathway and major depressive disorder

Tryptophan (TRP) is metabolized by two major pathways: the “kynurenine (KYN) pathway” and the “serotonin (5-HT)” pathways. 5-HT cannot pass the blood–brain barrier (BBB). The majority of TRP is metabolized to form KYN in the liver and is released into peripheral blood. The initial and rate-limiting step in the KYN pathway is catalyzed by indoleamine 2,3-dioxygenase 1 (IDO1), IDO2 and/or tryptophan 2,3-dioxygenase (TDO2)—depending on the tissue involved—to form N-formyl-kynurenine. N-formyl-kynurenine is metabolized by formamidase to produce KYN, which can cross the BBB. Approximately 60% of KYN in the CNS originates from the liver. In the periphery and in the CNS, KYN can be further metabolized by either kynurenine aminotransferases (KATs) or by kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU), leading to the generation of the neuroactive metabolites kynurenic acid (KYNA) or quinolinic acid (QUIN), respectively. KYNA, which is neuroprotective, and QUIN, which is neuroactive in the CNS, have opposite effects on the NMDA receptor. Four KATs, encoded by AADAT, CCBL1, CCBL2, and GOT2, have been shown to catalyze the conversion of KYN to KYNA. The other branches of the KYN pathway involve KMO and KYNU, which catalyze the metabolism of kynurenine to form 3-hydroxykynurenine and 3-hydroxyanthranilic acid, respectively. KYNU can also metabolize KYN to form anthranilic acid, which can then be coverted to 3-hydroxyanthranilic acid by nonspecific hydroxylation. 3-Hydroxyanthranilic acid is metabolized further by 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) to form either QUIN or, after a series of reactions, picolinic acid