400px, The kynurenine pathway The kynurenine pathway is a

metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...

leading to the production of nicotinamide adenine dinucleotide (NAD⁺). Metabolites involved in the kynurenine pathway include

tryptophan 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 ...

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 ...

kynurenic acid Kynurenic acid (KYNA or KYN) is a product of the normal metabolism of amino acid -tryptophan. It has been shown that kynurenic acid possesses neuroactive activity. It acts as an antiexcitotoxic and anticonvulsant, most likely through acting as an ...

, xanthurenic acid,

quinolinic acid Quinolinic acid (abbreviated QUIN or QA), 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. Quinolinic acid is a downstream produc ...

, 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 disorder A mental disorder, also referred to as a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitt ...

Kynurenine pathway dysfunction

Disorders affecting the kynurenine pathway may be primary (of genetic origin) or secondary (due to inflammatory conditions). Peripheral

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

can lead to a build up of kynurenine in the brain, and this is associated with

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...

bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...

, and

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...

. Dysfunction of the pathway not only cause increasing metabolites such as quinolinic acid or kynurenic acid but also affects serotonin and melatonin synthesis. Kynurenine clearance in exercised muscle cells can suppress the build up in the brain.

Hydroxykynureninuria

Also known as ''kynureninase deficiency'', this extremely rare inherited disorder is caused by the defective enzyme

kynureninase Kynureninase or L-Kynurenine hydrolase (KYNU) () is a PLP dependent enzyme that catalyses the cleavage of kynurenine (Kyn) into anthranilic acid (Ant). It can also act on 3-hydroxykynurenine (to produce 3-hydroxyanthranilate) and some other (3 ...

which leads to a block in the pathway from

to nicotinic acid. As a result, tryptophan is no longer a source of nicotinic acid and deficiency of the vitamin can develop. Both B₆-responsive and B₆-unresponsive forms are known. Patients with this disorder excrete excessive amounts of xanthurenic acid, kynurenic acid, 3-hydroxykynurenine, and kynurenine after tryptophan loading and are said to suffer from tachycardia, irregular breathing, arterial hypotension, cerebellar ataxia, developmental retardation, coma, renal tubular dysfunction, renal or metabolic acidosis, and even death. The only biochemical abnormality noted in affected patients was a massive hyperkynureninuria, seen only during periods of coma or after intravenous protein loading. This disturbance was temporarily corrected by large doses of vitamin B₆. The activity of kynureninase in the liver was markedly reduced. The activity was appreciably restored by the addition of pyridoxal phosphate.

Acquired and inherited enzyme deficiencies

Downregulation of

kynurenine 3-monooxygenase In enzymology, a kynurenine 3-monooxygenase () is an enzyme that catalysis, catalyzes the chemical reaction :Kynurenine, -kynurenine + nicotinamide adenine dinucleotide phosphate, NADPH + hydrogen ion, H+ + oxygen, O2 3-Hydroxykynurenine, 3-hydr ...

(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

towards kynurenic acid and

anthranilic acid Anthranilic acid is an aromatic acid with the formula C6H4(NH2)(CO2H) and has a sweetish taste. The molecule consists of a benzene ring, ''ortho''-substituted with a carboxylic acid and an amine. As a result of containing both acidic and basic ...

. Deficiencies of one or more enzymes on the kynurenine pathway leads to an accumulation of intermediate metabolic products which can cause effects depending on their concentration, function and their inter-relation with other metabolic products. For example, kynurenine 3-monooxygenase deficiency is associated with disorders of the brain (such as schizophrenia and tic disorders) and of the liver. The mechanism behind this observation is typically a blockade or bottleneck situation at one or more enzymes on the kynurenine pathway due to the effects of

indoleamine 2,3-dioxygenase Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO ) 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' ...

(IDO) and tryptophan 2,3-dioxygenase (TDO) and/or due to genetic polymorphisms afflicting the particular genes. Dysfunctional states of distinct steps of the kynurenine pathway (such as kynurenine,

, 3-hydroxykynurenine) have been described for a number of disorders, for example: *

HIV dementia HIV-associated neurocognitive disorders (HAND) are neurological disorders associated with HIV infection and AIDS. It is a syndrome of progressive deterioration of memory, cognition, behavior, and motor function in HIV-infected individuals during ...

Tourette syndrome Tourette syndrome or Tourette's syndrome (abbreviated as TS or Tourette's) is a common neurodevelopmental disorder that begins in childhood or adolescence. It is characterized by multiple movement (motor) tics and at least one vocal (phonic) ...

Tic disorders Tic disorders are defined in the ''Diagnostic and Statistical Manual of Mental Disorders'' (DSM) based on type (motor or phonic) and duration of tics (sudden, rapid, nonrhythmic movements). Tic disorders are defined similarly by the World Health ...

Psychiatric disorders A mental disorder, also referred to as a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitti ...

(such as

anxiety disorders Anxiety disorders are a cluster of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal function are significantly impaired. Anxiety may cause physi ...

) * Multiple sclerosis *

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...

Encephalopathies Encephalopathy (; from grc, ἐνκέφαλος "brain" + πάθος "suffering") means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but r ...

Lipid metabolism Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown or storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In anim ...

* Liver fat metabolism * Systemic lupus erythematosus * Glutaric aciduria * Vitamin B₆ deficiency * Eosinophilia-myalgia syndrome *long COVID

Research

Research into roles of the kynurenine pathway in human physiology is ongoing.

Neurodegenerative diseases and Mental Disorders

Scientists are investigating the role of dysregulation of this pathway in aging, neurodegenerative diseases, mental disorders, somatic symptom disorders, and chronic fatigue syndrome (CFS).

Kynurenine/tryptophan ratio

Changes in the ratio of kynurenine versus tryptophan are reported for many diseases like arthritis,

HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...

/ AIDS, neuropsychiatric disorders, cancer and inflammations. The kynurenin/tryptophan is also an indicator for the activity of

(IDO).

Methods

Kynurenine metabolites can be quantified using liquid chromatography coupled to mass spectrometry.

Related substrates

In some species, the kynurenine pathway also processes 6-bromotryptophan, leading to the analogous series of brominated metabolites. These and subsequent derivatives are believed to be responsible for the

biofluorescence Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation. It is a form of luminescence. In most cases, the emitted light has a longer wavelength, and therefore a lower photon energy, tha ...

observed in the skin of the

swell shark The swell shark (''Cephaloscyllium ventriosum'') is a catshark in the family Scyliorhinidae. It is found in the tropical and subtropical eastern Pacific Ocean from between central California to southern Mexico, with an additional population off ...

and the

chain catshark The chain catshark or chain dogfish (''Scyliorhinus retifer'') is a small, reticulated catshark that is biofluorescent. The species is common in the Northwest Atlantic, Gulf of Mexico and Caribbean. It is harmless and rarely encountered by human ...

References

{{reflist Metabolic pathways Ageing