Tryptophan metabolism

Category: catabolism

Overview

Beyond the 5-HT / melatonin axis (see serotonin_melatonin_axis), the dominant route for tryptophan (~95% of dietary intake) is the kynurenine pathway → eventually NAD+ via de novo synthesis (see niacin_nad_synthesis). Tryptophan → N-formylkynurenine (IDO in immune cells, TDO in liver) → kynurenine. Branch points: KMO → 3-hydroxykynurenine → quinolinic acid (NMDA agonist; neurotoxic at high concentration) → NAD+. KAT → kynurenic acid (NMDA antagonist; potentially neuroprotective). IDO is upregulated by IFN-γ in tumors as an immune-evasion mechanism — basis for IDO inhibitor oncology trials (epacadostat, etc., mostly negative in phase III). Tryptophan depletion underlies the proposed mechanism of depression in chronic inflammation.

Organ Systems

Pathway Steps

  1. tryptophan → n-formylkynurenine — via TDO (hepatic, glucocorticoid-induced) or IDO (immune, IFN-γ-induced) — RATE-LIMITING. Of tryptophan’s three fates — protein, serotonin, and kynurenine — the kynurenine route consumes the majority (~95%). TDO (hepatic, cortisol-induced) and IDO (immune, IFN-induced) gate it, so stress and inflammation pull tryptophan away from serotonin synthesis.
  2. n-formylkynurenine → kynurenine — via formamidase. Kynurenine is the central branch point feeding either the NAD-synthesis/quinolinic arm or the kynurenic-acid arm; it is also an aryl-hydrocarbon-receptor ligand with immune-modulating effects and crosses into the CNS from the periphery.
  3. kynurenine → 3-hydroxykynurenine — via KMO — main path; eventually NAD+ via quinolinic acid. KMO directs flux toward 3-hydroxykynurenine and ultimately quinolinic acid → NAD — the route by which dietary tryptophan can substitute for niacin (cross-link niacin_nad_synthesis). 3-HK is a pro-oxidant intermediate.
  4. kynurenine → kynurenic-acid — via KAT — branch path; NMDA antagonist; potentially neuroprotective. The alternative KAT branch yields kynurenic acid, an NMDA/α7-nicotinic antagonist — potentially neuroprotective, but elevated levels are linked to cognitive symptoms; the balance with the quinolinic arm shapes the pathway’s net CNS effect.

References