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 (biology), cell. The reactants, products, and Metabolic intermediate, intermediates of an enzymatic reaction are known as metabolites, which are ...

leading to the production of

nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide (NAD) is a Cofactor (biochemistry), coenzyme central to metabolism. Found in all living cell (biology), cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphat ...

(NAD⁺).

Metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s 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 aromat ...

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-dioxygena ...

, kynurenic acid, xanthurenic acid, quinolinic acid, and 3-hydroxykynurenine. The kynurenine pathway is responsible for about 95% of total tryptophan catabolism. Disruption in the pathway is associated with certain genetic and

psychiatric disorder A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...

Kynurenine pathway dysfunction

Disorders affecting the kynurenine pathway may be primary (of genetic origin) or secondary (due to inflammatory conditions). Peripheral inflammation 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 depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

, and

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

. Dysfunction of the pathway not only causes increase in amounts of metabolites such as quinolinic acid and kynurenic acid but also affects synthesis of

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

and

melatonin Melatonin, an indoleamine, is a natural compound produced by various organisms, including bacteria and eukaryotes. Its discovery in 1958 by Aaron B. Lerner and colleagues stemmed from the isolation of a substance from the pineal gland of cow ...

. 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 which leads to a block in the pathway from

to nicotinic acid mononucleotide (NaMN). As a result, tryptophan is no longer a source of

niacin Nicotinic acid, or niacin, is an organic compound and a vitamer of vitamin B3, an essential human nutrient. It is produced by plants and animals from the amino acid tryptophan. Nicotinic acid is also a prescription medication. Amounts f ...

, hence not producing

NAD NAD or Nad may refer to: Geography * Nad, County Cork, a village in Ireland * North American Datum, a series of geographic coordinate systems * North Atlantic Drift, an Atlantic Ocean current * Hobli, a subdivision of a taluka in southern Ind ...

, leading to

pellagra Pellagra is a disease caused by a lack of the vitamin niacin (vitamin B3). Symptoms include inflamed skin, diarrhea, dementia, and sores in the mouth. Areas of the skin exposed to friction and radiation are typically affected first. Over tim ...

(niacin deficiency). 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 (KMO) can be caused by genetic polymorphisms,

cytokines Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

, 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 f ...

. 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 Tissue (biology), tissues and Cell (biology), cells, such as the small intestine, lungs, female genital tract or placenta. I ...

(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, kynurenic acid, quinolinic acid,

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

Tourette syndrome Tourette syndrome (TS), or simply 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. Common tics are blinkin ...

* Tic disorders *

Attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

(ADHD) *

Psychiatric disorders A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...

(such as

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

) *

Multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...

Encephalopathies Encephalopathy (; ) means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of overall brain dysfunction; this syndrome ...

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

* Liver fat metabolism *

Systemic lupus erythematosus Lupus, formally called systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common ...

* Glutaric aciduria * Vitamin B₆ deficiency * Eosinophilia-myalgia syndrome *

Long COVID Long may refer to: Measurement * Long, characteristic of something of great duration * Long, characteristic of something of great length * Longitude (abbreviation: long.), a geographic coordinate * Longa (music), note value in early music mens ...

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 Arthritis is a general medical term used to describe a disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, Joint effusion, swelling, and decreased range of motion of ...

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 im ...

AIDS The HIV, human immunodeficiency virus (HIV) is a retrovirus that attacks the immune system. Without treatment, it can lead to a spectrum of conditions including acquired immunodeficiency syndrome (AIDS). It is a Preventive healthcare, pr ...

, 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 Biofluorescence is fluorescence exhibited by a living organism: part of the organism absorbs light or other radiation at one wavelength and emits visible light at another, usually longer. The absorbed radiation is often blue or ultraviolet, while t ...

observed in the skin of the swell shark and the chain catshark.

References

{{reflist Metabolic pathways Ageing