The Biology and Biochemistry of Kynurenic Acid, a Potential Nutraceutical with Multiple Biological Effects

Abstract

Kynurenic acid (KYNA) is an antioxidant degradation product of tryptophan that has been shown to have a variety of cytoprotective, neuroprotective and neuronal signalling properties. However, mammalian transporters and receptors display micromolar binding constants; these are consistent with its typically micromolar tissue concentrations but far above its serum/plasma concentration (normally tens of nanomolar), suggesting large gaps in our knowledge of its transport and mechanisms of action, in that the main influx transporters characterized to date are equilibrative, not concentrative. In addition, it is a substrate of a known anion efflux pump (ABCC4), whose in vivo activity is largely unknown. Exogeneous addition of L-tryptophan or L-kynurenine leads to the production of KYNA but also to that of many other co-metabolites (including some such as 3-hydroxy-L-kynurenine and quinolinic acid that may be toxic). With the exception of chestnut honey, KYNA exists at relatively low levels in natural foodstuffs. However, its bioavailability is reasonable, and as the terminal element of an irreversible reaction of most tryptophan degradation pathways, it might be added exogenously without disturbing upstream metabolism significantly. Many examples, which we review, show that it has valuable bioactivity. Given the above, we review its potential utility as a nutraceutical, finding it significantly worthy of further study and development.

Keywords: ABCC4; SLC22A6; SLC22A8; cytoprotectant; kynurenic acid; nutraceutical; oxidative stress.

Figure 1

Kynurenic acid structure and tautomers.

Figure 2

Elements of the kynurenine pathway. While the cytoprotective kynurenic acid can be derived endogenously from tryptophan, the pathway involves the synthesis of kynurenine that can lead to other toxic products such as quinolinic acid and 3-hydroxykynurenine. Redrawn in part from [102]. * Indicates ring cyclisation.

Figure 3

The ‘terminal’ steps of the KP from tryptophan to kynurenic acid. 1. L-tryptophan is catalyzed to N-formyl-L-kynurenine (NFK) by tryptophan dioxygenase (TDO) or indole dioxygenase (IDO1, IDO2) (EC 1.13.11.11 and 1.13.11.52), depending on the organism/tissue. 2. NFK is then converted to L-kynurenine (KYN) by the kynurenine formamidase (E.C. 3.5.1.9). 3. Finally, KYN is catalyzed to the unstable 4-(2-aminophenyl)-2,4-dioxobutanoate intermediate by a kynurenine transaminase (KAT1-4) (E. C. 2.6.1.7), which is readily converted to KYNA by a spontaneous reaction. The spontaneous cyclization of the intermediate to KYNA is unique to KYNA biosynthesis, and it makes this reaction effectively irreversible meaning that exogenous KYNA will not be converted to L-kynurenine nor its toxic derivatives.

Figure 4

Transcript expression levels and Gini coefficient of SLC22A6 and SLC22A8. Data from [148,238].

Figure 5

2D chemical structures of kynurenic acid and riboflavin, indicating a common substructure.

Figure 6

Assessing the fate of KYNA when its precursors are added externally is fraught unless one knows the expression levels of all the relevant transporters, the direction in which they transport, and whether they are concentrative or equilibrative [223,228], and we only know the existence of some of them. The membrane is redrawn in part from the animation at https://www.youtube.com/watch?v=s23vNwLE-Jw, accessed on 19 August 2024.

Figure 7

A summary of the kynurenic acid concentrations of various foodstuffs. Data are compiled from the following references: squares [392], circles [36], diamonds [391].

Figure 8

Production of reactive oxygen species as part of ischemia-reperfusion injury. Redrawn from the CC-BY 4.0 paper [413].

Figure 9

Cheminformatic analysis of the structural similarity of kynurenic acid to those marketed drugs for which the Tanimoto similarity with the RDKit Pattern encoding exceeds 0.7.

Figure 10

In silico prediction of the KYNA interactome. (A). Venn diagram analysis of predicted KYNA interacting proteins from the SuperPred [769], SwissTargetPrediction [768] and PharmMapper [767] cheminformatic tools. (B). Functional enrichment analysis of all (n = 455) predicted KYNA interactors. The DAVID [773] knowledgebase was used to identify the top functional annotation clusters, significantly enriched among the predicted KYNA interactome.