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Tryptophan metabolites from the Kynurenine Pathway by the gut microbiota suppress inflammatory responses in the macrophages.
Kynurenines serve as precursors for signaling molecules and are the first step in de novo NAD+ synthesis. In mammalian cells, the kynurenine pathway is initiated by the rate-limiting enzymes tryptophan-2,3-dioxygenase (TDO) and interferon-responsive Indoleamine 2,3-Dioxygenase (IDO). This pathway is the major route for tryptophan catabolism.
In the last decades, the involvement of the kynurenine pathway in brain diseases, particularly brain tumors, has gained more attention. Tryptophan is also catabolized through the serotonin pathway, leading to the biosynthesis of neuroactive metabolites such as serotonin and melatonin
Dehhaghi et al. 2020
The first and rate-limiting step in the Kynurenine Pathway is catalyzed by Indoleamine 2,3-Dioxygenase (IDO) (i.e., IDO1), Indoleamine 2,3-dioxygenase 2 (IDO2), and Tryptophan 2,3 Dioxygenase (TDO). N-formylkynurenine is rapidly metabolized by formamidase into L -kynurenine, which can be transformed by kynurenine aminotransferases (KATs), Kynureninase (KYNU), and kynurenine 3-monooxygenase (KMO) into kynurenic acid, Anthranilic acid, and 3-hydroxykynurenine, respectively. 3-hydroxykynurenine can then be transformed by KATs into Xanthurenic acid or by KYNU into 3-hydroxyanthranilic acid, which can be converted by 3-hydroxyanthranilate oxidase (3-HAO) into 2-Amino-3-carboxymuconic semialdehyde, which spontaneously transforms into quinolinic acid. Nicotinamide adenine dinucleotide (NAD+), the final product of the pathway, is obtained by several enzymatic reactions.
The kynurenine pathway is the main route of Tryptophan metabolism that results in the biosynthesis of Nicotinamide Adenine Dinucleotide (NAD+) and various neuroactive intermediates
It is important to note that gut microorganisms utilize tryptophan as a substrate to produce indoles, Indole Derivatives, which are key molecules involved in signaling pathways between the GI tract and the immune system
Indoleamine 2,3-Dioxygenase (IDO) catalyses the conversion of tryptophan to N-Formylkynurenine
see also:
Tryptophan metabolism
Tryptophan Metabolism & Pathways