Disorders of the kynurenine metabolism

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A disruption of the kynurenine metabolism can either be the cause or the consequence of altered metabolic processes in the human body. Functions of the brain and the central nervous system are mostly affected , but other organ systems can also be involved.

causes

A disruption of the kynurenine metabolism in various metabolic steps has been described for numerous diseases and is of clinical relevance in humans. Typically, cytokine - induced changes in the tryptophan / kynurenine metabolism lead to an accumulation of the metabolic product that was generated in the previous metabolic step and that should actually serve as a substrate for the defective or dysregulated enzyme . Depending on the enzyme concerned, different metabolic products accumulate. The accumulation of xanthurenic acid, quinolinic acid , kynurenine, kynurenic acid and anthranilic acid is of particular importance . A reduced enzymatic activity of kynurenine-3-monooxygenase (KMO deficiency) typically leads to an accumulation of kynurenine and a shift in tryptophan metabolism towards kynurenic acid, anthranilic acid and their other metabolic products. Since the efficiency of some of the enzymes on the metabolic pathway from tryptophan to kynurenine to nicotinic acid is dependent on vitamin B6, a vitamin B6 deficiency can in some cases lead to a large amount of the excreted kynurenine in the urine. One consequence of the dysregulation of the tryptophan-kynurenine metabolism is the increased formation of kynurenic acid. which in turn inhibits the release of glutamate and dopamine in the synaptic cleft .

Primary disorder of the kynurenine metabolism

Primary disorders of the kynurenine metabolism can result from a genetic defect that changes the function of an enzyme (e.g. kynurenine-3-monooxygenase ) on the metabolic pathway from tryptophan via kynurenine to nicotinamide . This usually leads to diffuse neuropsychiatric symptoms, cognitive impairment and / or damage to peripheral organ systems. The specific symptoms depend on which metabolic step on the metabolic pathway of kynurenine is primarily impaired.

Secondary disorders of the kynurenine metabolism

Secondary disorders of the kynurenine metabolism are usually immunologically justified, in particular by the action of indolamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) on the enzymes of the kynurenine metabolism, e.g. B. in the context of an inflammatory process. Deviations in kynurenine metabolism are associated with various pathological changes in humans:

Hyperkynureninuria

The so-called hyperkynureninuria is an extremely rare disease of the kynurenine metabolism in which those affected excrete greatly increased amounts of kynurenine, 3-hydroxykunurenine and xanthurenic acid in the urine. This happens because of a genetic defect that results in the lack of the enzyme kynurerninase. As a result, the body can no longer convert tryptophan sufficiently into nicotinamide via the metabolic pathway of the kynurenine, which results in deficiencies with muscle weakness, high blood pressure , psychomotor developmental disorders , deafness , stereotypes and encephalopathies . Treatments with vitamin B6 and pyridoxal phosphate are described.

Kynurenine / tryptophan ratio (quotient)

Relative increases in kynurenine ( kynurenine / tryptophan ratio ) are known in numerous inflammatory (e.g. rheumatoid arthritis ), infectious (e.g. HIV / AIDS), neuropsychiatric and malignant diseases and are considered to be an indicator of activation of certain aspects of the Immune system, especially the so-called innate immune system. The kynurenine / tryptophan ratio has established itself in medical research as a marker for the activity of indolamine 2,3-dioxygenase (IDO). The amount of neopterin in the body also correlates strongly with the kynurenine metabolism.

Individual evidence

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