Tryptophan–kynurenine metabolism (KP)

The tryptophan–kynurenine metabolism pathway is the primary catabolic route for the essential amino acid tryptophan, responsible for over 95% of its degradation in the body (Schwarcz et al., 2012, Nature Reviews Neuroscience). The pathway is initiated by rate-limiting enzymes, primarily indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO), which convert tryptophan into kynurenine (Munn & Mellor, 2013, Journal of Clinical Investigation). This metabolic cascade produces several bioactive metabolites, including kynurenic acid, 3-hydroxykynurenine, and quinolinic acid, which serve as ligands for the aryl hydrocarbon receptor (AhR) and modulate glutamatergic neurotransmission (Stone & Darlington, 2002, Nature Reviews Drug Discovery). In oncology, tumors often upregulate IDO1 to deplete tryptophan and accumulate kynurenine, creating an immunosuppressive microenvironment that inhibits T-cell and natural killer cell function (Prendergast et al., 2017, Cancer Research). Beyond cancer, dysregulation of this pathway is linked to neurodegenerative diseases and psychiatric disorders due to the neurotoxic or neuroprotective effects of its downstream metabolites (Savitz, 2020, Biological Psychiatry). Pharmacological intervention typically involves small-molecule inhibitors of IDO1, TDO, or kynurenine 3-monooxygenase (KMO) to restore immune surveillance or normalize neuroactive metabolite levels (Platten et al., 2019, Nature Reviews Cancer).

Other names

Kynurenine pathwayTryptophan degradation pathwayTrp-Kyn pathway

Inhibition of rate-limiting enzymes (IDO1, TDO, KMO) to modulate the production of immunosuppressive or neuroactive metabolites.