Kynurenine / NAD / tryptophan metabolism

The kynurenine pathway processes 90–95 % of dietary tryptophan and branches in two clinically decisive directions: (1) the KAT route → kynurenic acid (neuroprotective, an NMDA antagonist) and (2) the KMO route → 3-OH-kynurenine → quinolinic acid (neurotoxic, an NMDA agonist, oxidative stress) → and onward → NAD⁺ (nicotinamide adenine dinucleotide). NAD⁺ is the central electron carrier of energy metabolism and is consumed by sirtuins (enzymes that control genes and metabolism by removing acetyl groups) and by DNA repair enzymes (PARP). IDO (indoleamine 2,3-dioxygenase) is the key enzyme, activated by inflammation (IFN-γ, IL-6, TNF-α), which redirects a larger share of tryptophan into the kynurenine pathway — at the expense of serotonin and melatonin. KMO (kynurenine 3-monooxygenase) then decides within the pathway whether the neuroprotective branch (kynurenic acid) or the neurotoxic one (quinolinic acid) dominates. A dysregulation of this pathway is investigated in connection with inflammatory depression, CFS, long COVID and burnout.

How the kynurenine pathway leads from tryptophan to NAD⁺

The pathway begins with TDO in the liver or IDO in immune and tissue cells, which open tryptophan up to kynurenine. Kynurenine branches: with vitamin B6, the kynurenine aminotransferases form kynurenic acid; kynureninase forms anthranilic acid; KMO, which needs FAD from vitamin B2, forms 3-hydroxykynurenine. From this, kynureninase with vitamin B6 makes 3-hydroxyanthranilic acid, which an iron-dependent enzyme converts into an unstable intermediate. This closes spontaneously into quinolinic acid – or is diverted to picolinic acid by the enzyme ACMSD. Quinolinate phosphoribosyltransferase finally converts quinolinic acid into the NAD⁺ precursor. It is mainly the liver that makes NAD⁺ from tryptophan in this way; in addition, the body uses niacin and nicotinamide from food.

Kynurenine pathway not very active – what happens in the body?

When little tryptophan enters the kynurenine pathway, more of it remains available for proteins, serotonin and melatonin. For NAD⁺ production the body then depends more on niacin and nicotinamide from food. If vitamin B6 or B2 is lacking, the pathway stalls at individual points: with B6 deficiency, kynurenine and 3-hydroxykynurenine build up and more xanthurenic acid is formed; with B2 deficiency, KMO works more slowly. If both tryptophan and niacin are scarce, the NAD⁺ supply can become so low that the skin, gut and nervous system are affected – this condition is called pellagra.

Kynurenine pathway highly active – what happens in the body?

With inflammation, interferon-γ, TNF-α and IL-6 switch on IDO and then KMO, and cortisol additionally increases TDO in the liver. More tryptophan becomes kynurenine, and tryptophan in the blood falls. Which end products are formed depends on the active cells: macrophages and microglia form more quinolinic acid via 3-hydroxykynurenine, which stimulates NMDA receptors, while astrocytes form kynurenic acid, which dampens them. In immune cells the pathway also serves to replenish NAD⁺ when consumption is high. Changes in this balance have been observed in studies in depression with raised inflammatory markers, in chronic exhaustion after infections and in neurodegenerative diseases.

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