An expanding range of targets for kynurenine metabolites of tryptophan

Abstract

The kynurenine pathway of tryptophan metabolism accounts for most of the tryptophan that is not committed to protein synthesis and includes compounds active in the nervous and immune systems. Kynurenine acts on the aryl hydrocarbon receptor, affecting metabolism of xenobiotics and promoting carcinogenesis. Quinolinic acid is an agonist at N-methyl-D-aspartate receptors (NMDAR), but is also pro-oxidant, has immunomodulatory actions and promotes the formation of hyperphosphorylated tau proteins. Kynurenic acid blocks NMDARs and 7-homomeric nicotinic cholinoceptors but is also an agonist at the orphan G-protein-coupled receptor GPR35. 3-hydroxykynurenine and 3-hydroxyanthranilic acid have pronounced redox activity and regulate T cell function. Cinnabarinic acid can activate metabotropic glutamate receptors.The aim of this review is to highlight the increasing range of molecular targets for components of the kynurenine pathway, in both the nervous and immune systems, in relation to their relevance to disease and drug development. 3 The kynurenine pathwayApart from the tryptophan used in protein synthesis, most of this amino acid in mammals is oxidised along the kynurenine pathway. Only around 1% of tryptophan is used for the synthesis of 5-hydroxytrpytamine (5-HT). For many years, most compounds along the pathway ( Figure 1) were thought to have little biological activity until quinolinic acid was shown to be an agonist at glutamate receptors sensitive to NMDA [1] and kynurenic acid was found to be an antagonist at these and other ionotropic glutamate receptors [2]. These two compounds have been the focus of attention on the kynurenine pathway for over 30 years [3,4]. In parallel with work on the central nervous system (CNS), however, there has been growing interest in the role of kynurenines in the immune system, and the last few years have seen the identification of more molecular targets acted on by quinolinic acid, kynurenic acid or other components of the pathway. The key enzymes, indoleamine-2,3-dioxygenase (IDO) and kynurenine-3-monoxygenase (KMO) are also potential drug targets.The aim of this review is to highlight the increasing range of molecular targets now recognised in the nervous and immune systems in relation to their relevance to disease and drug development. Kynurenine metabolites and their receptors in disease Quinolinic acidIn addition to its ability to activate NMDARs selectively, quinolinic acid can generate reactive oxygen species (ROS). This activity can produce substantial oxidation of cellular lipids, especially in the presence of transition metal ions [5]. 4The axon-sparing neuronal loss produced by quinolinic acid in vivo may be due partly to formation of ROS [6] although it certainly also involves activation of NMDARs.Acting on human primary astrocytes, excitotoxic concentrations of quinolinic acid can also promote the expression and secretion of some of the more potent Kynurenic acidTwo early studies of the anti-epileptic actions of kynurenic acid independently reported that i...

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“…Ninety-nine percent of dietary tryptophan that is not used in protein synthesis is catabolized along the kynurenine pathway to quinolinic acid. Red rectangles represent the enzymes and rectangles with gray background represent important metabolic end products (Modifi ed and adapted from Stone and Darlington 2002 ;Stone et al 2013 ) given in fi nding the selective and effi cient inhibitors of these pathways to incorporate into current cancer treatment protocols.…”