Kynurenine pathway / de novo NAD+ biosynthesis from tryptophan (TDO2/IDO1/AFMID/KMO/KYNU/HAAO/ACMSD/QPRT)

The kynurenine pathway is the major route of L-tryptophan catabolism and the sole de novo source of NAD+ in humans, converting tryptophan through a series of ring-opening and modification steps to quinolinate and then to nicotinate mononucleotide (NaMN), which enters the common NAD+ pathway. It also generates neuroactive branch metabolites (kynurenic acid, quinolinic acid) and is central to immune regulation. The committed first step — oxidative ring cleavage of L-tryptophan to N-formyl-L-kynurenine — is catalysed by two heme dioxygenases with distinct physiology: the hepatic, rate-limiting TDO2 (tryptophan 2,3-dioxygenase) and the broadly IFN-gamma-inducible, immunoregulatory IDO1 (indoleamine 2,3-dioxygenase). The formamidase AFMID then hydrolyses N-formyl-kynurenine to L-kynurenine. Flux toward NAD+ requires the FAD-dependent, outer-mitochondrial-membrane kynurenine 3-monooxygenase KMO to hydroxylate kynurenine to 3-hydroxykynurenine (diverting away from the kynurenic-acid branch made by the aminotransferases AADAT/GOT2), followed by the PLP-dependent kynureninase KYNU, which cleaves 3-hydroxykynurenine to 3-hydroxyanthranilate. The Fe(II)-dependent dioxygenase HAAO opens the aromatic ring of 3-hydroxyanthranilate to 2-amino-3-carboxymuconate semialdehyde (ACMS), which spontaneously cyclises to quinolinate — unless the zinc enzyme ACMSD decarboxylates ACMS instead, diverting flux away from NAD+ toward full oxidation (picolinate/ acetyl-CoA). Finally quinolinate phosphoribosyltransferase QPRT condenses quinolinate with PRPP to NaMN, completing de novo NAD+ synthesis and detoxifying excitotoxic quinolinate. Inherited HAAO and KYNU deficiencies cause a congenital NAD-deficiency malformation syndrome (niacin-preventable in models); the pathway's enzymes (IDO1, TDO2, KMO, ACMSD) are drug targets in cancer immunotherapy, neurodegeneration and metabolic disease.