Abstract
The catabolism of tryptophan has gained great importance in recent years due to the fact that the metabolites produced during this process, with neuroactive and redox properties, are involved in physiological and pathological events. One of these metabolites is kynurenic acid (KYNA), which is considered as a neuromodulator since it can interact with NMDA, nicotinic, and GPR35 receptors among others, modulating the release of neurotransmitters as glutamate, dopamine, and acetylcholine. Kynureninate production is attributed to kynurenine aminotransferases. However, in some physiological and pathological conditions, its high production cannot be explained just with kynurenine aminotransferases. This review focuses on the alternative mechanism whereby KYNA can be produced, either from D-amino acids or by means of other enzymes as D-amino acid oxidase or by the participation of free radicals. It is important to mention that an increase in KYNA levels in processes as brain development, aging, neurodegenerative diseases, and psychiatric disorders, which share common factors as oxidative stress, inflammation, immune response activation, and participation of gut microbiota that can also be related with the alternative routes of KYNA production, has been observed.
Highlights
The catabolism of tryptophan has gained great importance in recent years due to the fact that the metabolites produced during this process, with neuroactive and redox properties, are involved in physiological and pathological events
One of these metabolites is kynurenic acid (KYNA), which is considered as a neuromodulator since it can interact with NMDA, nicotinic, and GPR35 receptors among others, modulating the release of neurotransmitters as glutamate, dopamine, and acetylcholine
Due to KYNA can interact with N-methyl-Daspartate receptor (NMDAr), α7nAChRs and AMPAr[9,13,14]and since its levels secondarily affect the extracellular concentrations of glutamate, dopamine, acetylcholine and γ-aminobutyric acid (GABA) is considered as neuromodulator[10,11,12,13,14,15,16,17,18,19]
Summary
The canonical route of KYNA formation is through the kynurenine pathway by kynurenine aminotransferases. These enzymes catalyze the irreversible transamination of kynurenine to produce KYNA. KATs have a low affinity for their substrate (approximately 1 mM) so that the rate of KYNA formation is directly controlled by local kynurenine availability [35, 36]. Considering the low affinity for the substrate shown by the KATs and the evidence that the kynurenic acid produced by D-Kyn is not completely inhibited by the KAT inhibitor, it is feasible to suggest that there are alternative mechanisms by which KYNA can be produced and they could be relevant in physiological conditions as well as in pathological events
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