A Review on the Role and Function of Cinnabarinic Acid, a "Forgotten" Metabolite of the Kynurenine Pathway

Abstract

In the human body, the majority of tryptophan is metabolized through the kynurenine pathway. This consists of several metabolites collectively called the kynurenines and includes, among others, kynurenic acid, L-kynurenine, or quinolinic acid. The wealth of metabolites, as well as the associated molecular targets and biological pathways, bring about a situation wherein even a slight imbalance in the kynurenine levels, both in the periphery and central nervous system, have broad consequences regarding general health. Cinnabarinic acid (CA) is the least known trace kynurenine, and its physiological and pathological roles are not widely understood. Some studies, however, indicate that it might be neuroprotective. Information on its hepatoprotective properties have also emerged, although these are pioneering studies and need to be replicated. Therefore, in this review, I aim to present and critically discuss the current knowledge on CA and its role in physiological and pathological settings to guide future studies.

Keywords: aryl hydrocarbon receptor; cinnabarinic acid; kynurenine pathway; metabotropic glutamate receptor; schizophrenia.

Figure 1

An overview of the synthesis of kynurenine pathway metabolites. The major metabolites are highlighted in yellow (note: cinnabarinic acid is accentuated in green). The following enzymes are spotlighted: 3-HAO—3-hydroxyanthranilate oxidase; ACMSD—aminocarboxy-muconate-semialdehyde decarboxylase; IDO—indoleamine-2,3-dioxygensase; KATs—kynurenine aminotransferases; KMO—kynurenine-3-monooxygenase; KYNU—kynureninase; NAD—nicotinamide adenine dinucleotide; TDO—tryptophan-2,3-dioxygenase; QPRT—quinolinate phosphoribosyltransferase.

Figure 2

Chemical structure and overview of molecular targets and mechanisms of action of cinnabarinic acid. (+) means increases/stimulates, (−) means inhibits, (?) means contradictory data that need further investigation. For details, see text and Table 1. AhR—aryl hydrocarbon; IDO—indoleamine-2,3-dioxygenase; IL22—interleukine 22; mGlu4—metabotropic glutamate receptor type 4; ROS—reactive oxygen species.