Kynurenine

Last updated
l-Kynurenine
L-Kynurenine.svg
L-Kynurenine-zwitterion-3D-balls.png
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
  • InChI=1S/C10H12N2O3/c11-7-4-2-1-3-6(7)9(13)5-8(12)10(14)15/h1-4,8H,5,11-12H2,(H,14,15)/t8-/m0/s1 Yes check.svgY
    Key: YGPSJZOEDVAXAB-QMMMGPOBSA-N Yes check.svgY
  • c1ccc(c(c1)C(=O)C[C@@H](C(=O)O)N)N
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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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

Contents

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] Kynurenine and its further breakdown products carry out diverse biological functions, including dilating blood vessels during inflammation [2] and regulating the immune response. [3] Some cancers increase kynurenine production, which increases tumor growth. [1]

Kynurenine protects the eye by absorbing UV light, especially in the UVA region (315-400 nm). [4] 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. [5] [6] 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. [7] The concentration of this UV filter decreases with age, [8] 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. [9] [10] [11]

Evidence suggests that increased kynurenine production may precipitate depressive symptoms associated with interferon treatment for hepatitis C. [12] Cognitive deficits in schizophrenia are associated with imbalances in the enzymes that break down kynurenine. [13] Blood levels of kynurenine are reduced in people with bipolar disorder. [14] Kynurenine production is increased in Alzheimer's disease [15] and cardiovascular disease [16] where its metabolites are associated with cognitive deficits [17] and depressive symptoms. [18] Kynurenine is also associated with tics. [19] [20]

Kynureninase catabolizes the conversion of kynurenine into anthranilic acid [21] while kynurenine-oxoglutarate transaminase catabolizes its conversion into kynurenic acid. Kynurenine 3-hydroxylase converts kynurenine to 3-hydroxykynurenine. [22]

Kynurenine has also been identified as one of two compounds that makes up the pigment that gives the goldenrod crab spider its yellow color. [23]

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. Kynurenine pathway wordless.svg
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.

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: [25]

Downregulation of kynurenine-3-monooxygenase (KMO) can be caused by genetic polymorphisms, cytokines, or both. [28] [29] KMO deficiency leads to an accumulation of kynurenine and to a shift within the tryptophan metabolic pathway towards kynurenine acid and anthranilic acid. [30] Kynurenine-3-monooxygenase deficiency is associated with disorders of the brain (e.g. major depressive disorder, bipolar disorder, schizophrenia, tic disorders) [31] and of the liver. [19] [32] [33] [34] [35]

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. [36] [37]

See also

Related Research Articles

<span class="mw-page-title-main">Tryptophan</span> Chemical compound

Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromatic beta carbon substituent. Tryptophan is also a precursor to the neurotransmitter serotonin, the hormone melatonin, and vitamin B3. It is encoded by the codon UGG.

Schizoaffective disorder is a mental disorder characterized by abnormal thought processes and an unstable mood. This diagnosis requires symptoms of both schizophrenia and a mood disorder: either bipolar disorder or depression. The main criterion is the presence of psychotic symptoms for at least two weeks without any mood symptoms. Schizoaffective disorder can often be misdiagnosed when the correct diagnosis may be psychotic depression, bipolar I disorder, schizophreniform disorder, or schizophrenia. This is a problem as treatment and prognosis differ greatly for most of these diagnoses.

<span class="mw-page-title-main">Kynurenic acid</span> Chemical compound

Kynurenic acid is a product of the normal metabolism of amino acid L-tryptophan. It has been shown that kynurenic acid possesses neuroactive activity. It acts as an antiexcitotoxic and anticonvulsant, most likely through acting as an antagonist at excitatory amino acid receptors. Because of this activity, it may influence important neurophysiological and neuropathological processes. As a result, kynurenic acid has been considered for use in therapy in certain neurobiological disorders. Conversely, increased levels of kynurenic acid have also been linked to certain pathological conditions.

<span class="mw-page-title-main">Indoleamine 2,3-dioxygenase</span> Mammalian protein found in Homo sapiens

Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO EC 1.13.11.52) is a heme-containing enzyme physiologically expressed in a number of tissues and cells, such as the small intestine, lungs, female genital tract or placenta. In humans is encoded by the IDO1 gene. IDO is involved in tryptophan metabolism. It is one of three enzymes that catalyze the first and rate-limiting step in the kynurenine pathway, the O2-dependent oxidation of L-tryptophan to N-formylkynurenine, the others being indolamine-2,3-dioxygenase 2 (IDO2) and tryptophan 2,3-dioxygenase (TDO). IDO is an important part of the immune system and plays a part in natural defense against various pathogens. It is produced by the cells in response to inflammation and has an immunosuppressive function because of its ability to limit T-cell function and engage mechanisms of immune tolerance. Emerging evidence suggests that IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system. Expression of IDO has been described in a number of types of cancer, such as acute myeloid leukemia, ovarian cancer or colorectal cancer. IDO is part of the malignant transformation process and plays a key role in suppressing the anti-tumor immune response in the body, so inhibiting it could increase the effect of chemotherapy as well as other immunotherapeutic protocols. Furthermore, there is data implicating a role for IDO1 in the modulation of vascular tone in conditions of inflammation via a novel pathway involving singlet oxygen.

<span class="mw-page-title-main">Aromatic amino acid</span> Amino acid having an aromatic ring

An aromatic amino acid is an amino acid that includes an aromatic ring.

<i>N</i>-Formylkynurenine Chemical compound

N′-Formylkynurenine is an intermediate in the catabolism of tryptophan. It is a formylated derivative of kynurenine. The formation of N′-formylkynurenine is catalyzed by heme dioxygenases.

<span class="mw-page-title-main">Kynurenine 3-monooxygenase</span> Enzyme

In enzymology, a kynurenine 3-monooxygenase (EC 1.14.13.9) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Tryptophan 2,3-dioxygenase</span> Mammalian protein found in Homo sapiens

In enzymology, tryptophan 2,3-dioxygenase (EC 1.13.11.11) is a heme enzyme that catalyzes the oxidation of L-tryptophan (L-Trp) to N-formyl-L-kynurenine, as the first and rate-limiting step of the kynurenine pathway.

<span class="mw-page-title-main">Dioxygenase</span> Class of enzymes

Dioxygenases are oxidoreductase enzymes. Aerobic life, from simple single-celled bacteria species to complex eukaryotic organisms, has evolved to depend on the oxidizing power of dioxygen in various metabolic pathways. From energetic adenosine triphosphate (ATP) generation to xenobiotic degradation, the use of dioxygen as a biological oxidant is widespread and varied in the exact mechanism of its use. Enzymes employ many different schemes to use dioxygen, and this largely depends on the substrate and reaction at hand.

<span class="mw-page-title-main">Xanthurenic acid</span> Chemical compound

Xanthurenic acid, or xanthurenate, is a metabolic intermediate that accumulates and is excreted by pyridoxine (vitamin B6) deficient animals after the ingestion of tryptophan.

<span class="mw-page-title-main">Quinolinic acid</span> Dicarboxylic acid with pyridine backbone

Quinolinic acid, also known as pyridine-2,3-dicarboxylic acid, is a dicarboxylic acid with a pyridine backbone. It is a colorless solid. It is the biosynthetic precursor to niacin.

<span class="mw-page-title-main">KMO (gene)</span> Protein-coding gene in the species Homo sapiens

Kynurenine 3-monooxygenase is an enzyme that in humans is encoded by the KMO gene.

<span class="mw-page-title-main">3-Hydroxykynurenine</span> Chemical compound

3-Hydroxykynurenine is a metabolite of tryptophan, which filters UV light in the human lens. It is one of two pigments identified as responsible for the goldenrod crab spider's yellow coloration.

<span class="mw-page-title-main">Hypertryptophanemia</span> Medical condition

Hypertryptophanemia is a rare autosomal recessive metabolic disorder that results in a massive buildup of the amino acid tryptophan in the blood, with associated symptoms and tryptophanuria.

<span class="mw-page-title-main">Kynurenine pathway</span> Metabolic pathway that produces the NAD coenzyme

The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+). Metabolites involved in the kynurenine pathway include tryptophan, kynurenine, kynurenic acid, xanthurenic acid, quinolinic acid, and 3-hydroxykynurenine. The kynurenine pathway is responsible for total catabolization of tryptophan about 95%. Disruption in the pathway is associated with certain genetic and psychiatric disorders.

<span class="mw-page-title-main">Cariprazine</span> Atypical antipsychotic medicine

Cariprazine, sold under the brand names Vraylar,Reagila and Symvenu among others, is an atypical antipsychotic developed by Gedeon Richter, which is used in the treatment of schizophrenia, bipolar mania, bipolar depression, and major depressive disorder. It acts primarily as a D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors, with high selectivity for the D3 receptor. It is taken by mouth.

<span class="mw-page-title-main">Kraepelinian dichotomy</span>

The Kraepelinian dichotomy is the division of the major endogenous psychoses into the disease concepts of dementia praecox, which was reformulated as schizophrenia by Eugen Bleuler by 1908, and manic-depressive psychosis, which has now been reconceived as bipolar disorder. This division was formally introduced in the sixth edition of Emil Kraepelin's psychiatric textbook Psychiatrie. Ein Lehrbuch für Studirende und Aerzte, published in 1899. It has been highly influential on modern psychiatric classification systems, the DSM and ICD, and is reflected in the taxonomic separation of schizophrenia from affective psychosis. However, there is also a diagnosis of schizoaffective disorder to cover cases that seem to show symptoms of both.

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<span class="mw-page-title-main">Indoleamine 2,3-dioxygenase 2</span> Protein-coding gene in the species Homo sapiens

Indoleamine 2,3-dioxygenase 2 (IDO2) is a protein that in humans is encoded by the IDO2 gene.

References

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  30. ↑ Wonodi I, Stine OC, Sathyasaikumar KV, Roberts RC, Mitchell BD, Hong LE, Kajii Y, Thaker GK, Schwarcz R (2011). "Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes". Arch. Gen. Psychiatry. 68 (7): 665–74. doi:10.1001/archgenpsychiatry.2011.71. PMC   3855543 . PMID   21727251.
  31. ↑ Marx W, McGuinness AJ, Rocks T, Ruusunen A, Cleminson J, Walker AJ, Gomes-da-Costa S, Lane M, Sanches M, Diaz AP, Tseng PT, Lin PY, Berk M, Clarke G, O'Neil A, Jacka F, Stubbs B, Carvalho AF, Quevedo J, Soares JC, Fernandes BS (2020). "The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies". Molecular Psychiatry. 26 (8): 4158–4178. doi:10.1038/s41380-020-00951-9. PMID   33230205. S2CID   227132820 – via doi: 10.1038/s41380-020-00951-9. PMID 33230205.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  36. ↑ Bartoli, Francesco; Cioni, Riccardo M.; Cavaleri, Daniele; Callovini, Tommaso; Crocamo, Cristina; Misiak, Błażej; Savitz, Jonathan B.; Carrà, Giuseppe (January 2022). "The association of kynurenine pathway metabolites with symptom severity and clinical features of bipolar disorder: An overview". European Psychiatry. 65 (1): e82. doi: 10.1192/j.eurpsy.2022.2340 . ISSN   0924-9338.
  37. ↑ Fornaro, Michele; Kardash, Lubna; Novello, Stefano; Fusco, Andrea; Anastasia, Annalisa; De Berardis, Domenico; Perna, Giampaolo; Carta, Mauro Giovanni (4 March 2018). "Progress in bipolar disorder drug design toward the development of novel therapeutic targets: a clinician's perspective". Expert Opinion on Drug Discovery. 13 (3): 221–228. doi:10.1080/17460441.2018.1428554.
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