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Kynurenine

-Kynurenine is a metabolite of the amino acid -tryptophan used in the production of niacin.

Kynurenine is synthesized by the enzyme tryptophan dioxygenase, which is made primarily but not exclusively in the liver, and indoleamine 2,3-dioxygenase, which is made in many tissues in response to immune activation. An important source is the intestine. Kynurenine and its further breakdown products carry out diverse biological functions, including dilating blood vessels during inflammation and regulating the immune response. Some cancers increase kynurenine production, which increases tumor growth.

Kynurenine protects the eye by absorbing UV light, especially in the UVA region (315–400 nm). Kynurenine is present in the lens and retina as one of multiple tryptophan derivatives produced in the eye, including 3-hydroxykynurenine, that together provide UV protection and aid in enhancing visual acuity. The use of kynurenine as a UV filter is consistent with its photostability and low photosensitization, owing to its efficient relaxation from the UV-induced excited state. The concentration of this UV filter decreases with age, and this loss of free kynurenine and the concomitant formation of relatively more photosensitizing kynurenine derivatives and kynurenine-protein conjugates may contribute to the formation of cataracts.

Evidence suggests that increased kynurenine production may precipitate depressive symptoms associated with interferon treatment for hepatitis C. Cognitive deficits in schizophrenia are associated with imbalances in the enzymes that break down kynurenine. Blood levels of kynurenine are reduced in people with bipolar disorder. Kynurenine production is increased in Alzheimer's disease and cardiovascular disease where its metabolites are associated with cognitive deficits and depressive symptoms. Kynurenine is also associated with tics. Myokines regulate its metabolism.

Kynureninase catalyzes the conversion of kynurenine into anthranilic acid while kynurenine-oxoglutarate transaminase catalyzes its conversion into kynurenic acid. Kynurenine 3-hydroxylase catalyzes the conversion of kynurenine to 3-hydroxykynurenine.

Kynurenine has also been identified as one of two compounds that makes up the pigment that gives the goldenrod crab spider its yellow color.

thumb|280px|left|The [[kynurenine pathway]], which connects [[quinolinic acid]] to tryptophan. The pathway is named for the first intermediate, kynurenine, which is a precursor to [[kynurenic acid]] and [[3-Hydroxykynurenine|3-hydroxykynurenine]].

Kynurenine pathway dysfunction

Dysfunctional states of distinct steps of the kynurenine pathway (such as kynurenine, kynurenic acid, quinolinic acid, anthranilic acid, 3-hydroxykynurenine) have been described for a number of disorders, including:

  • HIV dementia
  • Tourette syndrome
  • Tic disorders
  • Psychiatric disorders (such as schizophrenia, bipolar disorder, major depression, anxiety disorders)
  • Multiple sclerosis
  • Huntington's disease
  • Encephalopathies
  • Lipid metabolism
  • Liver fat metabolism
  • Systemic lupus erythematosus
  • Glutaric aciduria
  • Vitamin B6 deficiency
  • Eosinophilia-myalgia syndrome
  • Myalgic encephalomyelitis/chronic fatigue syndrome

Downregulation of kynurenine-3-monooxygenase (KMO) can be caused by genetic polymorphisms, cytokines, or both. KMO deficiency leads to an accumulation of kynurenine and to a shift within the tryptophan metabolic pathway towards kynurenine acid and anthranilic acid. Kynurenine-3-monooxygenase deficiency is associated with disorders of the brain (e.g. major depressive disorder, bipolar disorder, schizophrenia, tic disorders) and of the liver.

Drug development

It is hypothesized that the kynurenine pathway is partly responsible for the therapeutic effect of lithium on bipolar disorder. If that is the case, it could be a target of drug discovery.

References

References

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aldehyde-dehydrogenase-inhibitors alpha-amino-acids 2-aminophenyl-compounds human-metabolites nmda-receptor-antagonists
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