Kynurenine
Chemical compound
From Wikipedia, the free encyclopedia
l-Kynurenine is a metabolite of the amino acid l-tryptophan used in the production of niacin.
| |
 | |
| Names | |
|---|---|
| Preferred IUPAC name
(2S)-2-Amino-4-(2-aminophenyl)-4-oxo-butanoic acid | |
| Other names
(S)-Kynurenine | |
| Identifiers | |
| |
3D model (JSmol) |
|
| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| DrugBank | |
| MeSH | Kynurenine |
PubChem CID |
|
| UNII | |
CompTox Dashboard (EPA) |
|
| |
| |
| Properties | |
| C10H12N2O3 | |
| Molar mass | 208.217 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
| |
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.[1] An important source is the intestine.[2] Kynurenine and its further breakdown products carry out diverse biological functions, including dilating blood vessels during inflammation[3] and regulating the immune response.[4] Some cancers increase kynurenine production, which increases tumor growth.[1][5]
Biosynthesis
Kynurenine gives its name to the kynurenine pathway which leads from the amino acid tryptophan to many important enzyme cofactors including niacin and nicotinamide adenine dinucleotide.[6]
Three enzymes present in different organisms and tissues are known to catalyse the oxidation of the pyrrole ring in tryptophan, giving the N-formyl deriative which is subsequently hydrolysed to kynurenine. These are tryptophan dioxygenase, indoleamine 2,3-dioxygenase and indoleamine 2,3-dioxygenase 2.[1][2]
Metabolism
In the main pathway to quinolinic acid, the next step is an oxidation reaction catalysed by kynurenine 3-hydroxylase, which uses oxygen and nicotinamide adenine dinucleotide phosphate (NADPH) to place a phenolic group next to the aromatic amine.[6][8]
In an alternative metabolic process which is enhanced in inflammatory responses, the enzyme kynureninase produces anthranilic acid and L-alanine.[3][9]
A third outcome for metabolism is by the action of kynurenine-oxoglutarate transaminase, which gives kynurenic acid by transamination with α-ketoglutaric acid.[10]
Clinical effects
Kynurenine protects the eye by absorbing UV light, especially in the UVA region (315–400 nm).[11] 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.[12][13] 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.[14] The concentration of this UV filter decreases with age,[15] 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.[16][17][18]
Evidence suggests that increased kynurenine production may precipitate depressive symptoms associated with interferon treatment for hepatitis C.[19] Cognitive deficits in schizophrenia are associated with imbalances in the enzymes that break down kynurenine.[20] Blood levels of kynurenine are reduced in people with bipolar disorder.[21] Kynurenine production is increased in Alzheimer's disease[22][23] and cardiovascular disease[24] where its metabolites are associated with cognitive deficits[25] and depressive symptoms.[26] Kynurenine is also associated with tics.[27][28] Myokines regulate its metabolism.[29][30][31]
Kynurenine has also been identified as one of two compounds that makes up the pigment that gives the goldenrod crab spider its yellow color.[32]
Kynurenine pathway dysfunction
Dysfunctional states of distinct steps of the kynurenine pathway have been described for a number of disorders, including:[33]
- Psychiatric disorders (such as schizophrenia, bipolar disorder,[21] major depression,[34] anxiety disorders)
- Myalgic encephalomyelitis/chronic fatigue syndrome[35]
Downregulation of kynurenine-3-monooxygenase (KMO) can be caused by genetic polymorphisms, cytokines, or both.[36] KMO deficiency leads to an accumulation of kynurenine and to a shift within the tryptophan metabolic pathway towards kynurenine acid and anthranilic acid.[37] This deficiency is associated with disorders of the brain (e.g. major depressive disorder, bipolar disorder, schizophrenia, tic disorders)[38] and of the liver.[27][39][40][41]
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.[42][43]