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Endogenous kynurenines as targets for drug discovery and development

Key Points

At-a-glance

  • Kynurenines are the main products of tryptophan metabolism.

  • The kynurenine pathway is activated by interferon-γ and other immune-system mediators.

  • Quinolinic acid is an agonist at N-methyl-d-aspartate (NMDA) receptors, and is excitatory and neurotoxic.

  • Kynurenic acid is an antagonist at glutamate receptors and nicotinic acetylcholine (nACh) receptors, and might act at other unidentified sites.

  • Quinolinic acid, acting at NMDA receptors during brain development, could contribute to neuronal growth and synaptogenesis.

  • 3-Hydroxykynurenine generates free radicals and is also neurotoxic.

  • The levels of kynurenines are elevated in disorders that involve brain damage, and might contribute to that damage. For example, quinolinic acid or 3-hydroxykynurenine levels are increased in AIDS–dementia, Huntington's disease and traumatic brain injury.

  • Kynurenic acid levels are raised in Down syndrome, neonatal asphyxia and schizophrenia.

  • As glutamate and nACh receptors are present in peripheral tissues, some peripheral disorders might be associated with altered kynurenine activity.

  • Several components of the pathway could contribute to type 2 diabetes.

  • Depletion of tryptophan inhibits cell growth and division.

  • As the predominant metabolites of tryptophan metabolic pathways also yield 5-hydroxytryptamine and melatonin, changes in the kynurenine pathway could influence the biology of all indole derivatives.

Abstract

The kynurenine pathway is the main pathway for tryptophan metabolism. It generates compounds that can modulate activity at glutamate receptors and possibly nicotinic receptors, in addition to some as-yet-unidentified sites. The pathway is in a unique position to regulate other aspects of the metabolism of tryptophan to neuroactive compounds, and also seems to be a key factor in the communication between the nervous and immune systems. It also has potentially important roles in the regulation of cell proliferation and tissue function in the periphery. As a result, the pathway presents a multitude of potential sites for drug discovery in neuroscience, oncology and visceral pathology.

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Figure 1: A summary of the various pathways of tryptophan metabolism.
Figure 2: Kynurenines and nitric oxide.
Figure 3: NMDA-receptor antagonists.
Figure 4: Kynurenine-pathway inhibitors.
Figure 5: The possible roles of kynurenines in diabetes.

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Acknowledgements

The authors' current research on kynurenines that is included in this review is supported by the NHS R&D Levy, the Peacock Trust and the Denbies Foundation.

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Correspondence to Trevor W. Stone.

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DATABASES

FlyBase

cardinal

LocusLink

α1-adrenoceptor

α2-adrenoceptor

COX

crystallins

5-HT2A receptor

5-HT2B receptor

huntingtin

3-hydroxyanthranilic acid 3,4-dioxygenase

IDO

IFN-γ

IL-1β

IL-4

insulin

KATII

kynurenine 3-hydroxylase

MAO

α7-nACh receptor

nerve growth factor

NF-γB

NMDA receptors

NOS

phosphoenolpyruvate carboxykinase

phospholipase C

QPRT

superoxide dismutase

TDO

TGF-β

TNF-α

TP53

tryptophan hydroxylase

Medscape DrugInfo

aspirin

OMIM

Alzheimer's disease

Down syndrome

Huntington's disease

multiple sclerosis

olivopontocerebellar atrophy

Parkinson's disease

psoriasis

rheumatoid arthritis

Tourette's syndrome

type 2 diabetes

FURTHER INFORMATION

Encyclopedia of Life Sciences

nervous and immune system interactions

Glossary

SUPEROXIDE

A highly reactive oxygen free radical, of the formula O2−·.

GLYB SITE

The allosteric receptor site for glycine on the NMDA receptor. At this site, glycine acts as an essential co-agonist for the activation of the receptor by glutamate. The site is also known as the strychnine-resistant glycine site, to distinguish it from the inhibitory glycineA receptor, which is blocked by strychnine.

GLUCONEOGENESIS

The generation of glucose from non-carbohydrate sources, mainly amino acids.

MYENTERIC PLEXUS

One of the two main networks of neurons that are present in the walls of the intestine; responsible for regulating the rhythm and force of its contractions and cellular secretions.

DYSRHYTHMIAS

Abnormal rhythms, usually of the heart.

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Stone, T., Darlington, L. Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov 1, 609–620 (2002). https://doi.org/10.1038/nrd870

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