Kynurenine 3-monooxygenase

KMO (kynurenine 3-monooxygenase) is the key enzyme of the kynurenine pathway – the main route by which tryptophan is broken down during inflammation. It converts kynurenine into 3-hydroxykynurenine, which is further broken down to quinolinic acid (QUIN) – a strong NMDA agonist with a neurotoxic effect. KMO activity is upregulated by inflammatory cytokines (IL-6, TNF-α). High KMO activity means: kynurenine flows increasingly into the branch towards 3-hydroxykynurenine and quinolinic acid instead of towards kynurenic acid. Investigated in connection with depression, neuroinflammation and long COVID.

How kynurenine 3-monooxygenase works

KMO is an enzyme in the outer membrane of the mitochondria. It attaches a hydroxyl group to kynurenine and needs oxygen, NADPH as an electron donor and FAD as a cofactor to do so – FAD is made from vitamin B2. The liver and kidneys contain the most KMO. In the brain the work is divided: microglial cells and macrophages that have migrated there possess KMO and form the branch towards 3-hydroxykynurenine and quinolinic acid, while astrocytes have hardly any KMO and mainly make kynurenic acid from kynurenine. Which cells are currently active therefore helps determine which metabolites predominate in nerve tissue.

Low KMO activity – what happens in the body?

When KMO works slowly, kynurenine builds up before this step and is increasingly converted by the kynurenine aminotransferases into kynurenic acid and by kynureninase into anthranilic acid. Low activity occurs when vitamin B2 is scarce and the enzyme lacks FAD, and with inherited variants of the KMO gene. In studies, reduced KMO activity and raised kynurenic acid in the cerebrospinal fluid have been observed in schizophrenia; whether the dampened glutamate signalling is connected with changes in thinking is being discussed there.

High KMO activity – what happens in the body?

Inflammatory messengers such as interferon-γ, TNF-α and IL-6 increase the amount of KMO in macrophages and microglia. The enzyme then converts more kynurenine into 3-hydroxykynurenine, and more quinolinic acid is formed. 3-hydroxykynurenine generates reactive oxygen species, and quinolinic acid stimulates NMDA receptors and lets calcium flow into nerve cells; at the same time KMO itself consumes NADPH and oxygen. Since only activated microglia and macrophages have KMO in the brain, high activity there mainly reflects an inflammatory reaction in nerve tissue.

The interpretation is given in your report.