Abstract
Kynurenines, the main products of tryptophan catabolism, possess both prooxidant and anioxidant effects. Having multiple neuroactive properties, kynurenines are implicated in the development of neurological and cognitive disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. Autoxidation of 3-hydroxykynurenine (3HOK) and its derivatives, 3-hydroxyanthranilic acid (3HAA) and xanthommatin (XAN), leads to the hyperproduction of reactive oxygen species (ROS) which damage cell structures. At the same time, 3HOK and 3HAA have been shown to be powerful ROS scavengers. Their ability to quench free radicals is believed to result from the presence of the aromatic hydroxyl group which is able to easily abstract an electron and H-atom. In this study, the redox properties for kynurenines and several natural and synthetic antioxidants have been calculated at different levels of density functional theory in the gas phase and water solution. Hydroxyl bond dissociation enthalpy (BDE) and ionization potential (IP) for 3HOK and 3HAA appear to be lower than for xanthurenic acid (XAA), several phenolic antioxidants, and ascorbic acid. BDE and IP for the compounds with aromatic hydroxyl group are lower than for their precursors without hydroxyl group. The reaction rate for H donation to *O-atom of phenoxyl radical (Ph-O*) and methyl peroxy radical (Met-OO*) decreases in the following rankings: 3HOK ~ 3HAA > XAAOXO > XAAENOL. The enthalpy absolute value for Met-OO* addition to the aromatic ring of the antioxidant radical increases in the following rankings: 3HAA* < 3HOK* < XAAOXO* < XAAENOL*. Thus, the high free radical scavenging activity of 3HAA and 3HOK can be explained by the easiness of H-atom abstraction and transfer to O-atom of the free radical, rather than by Met-OO* addition to the kynurenine radical.
Highlights
The kynurenine pathway (KP), the primary route of tryptophan degradation in mammalian cells, includes kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3HOK), 3-hydroxyanthranilic acid (3HAA), quinolinic acid (QUIN), and other metabolites collectively called kynurenines (Fig 1).There are multiple mechanisms of kynurenines’ action on nervous system
There is lack of computational studies of kynurenines properties which could help us better understand the biophysical mechanism of their antioxidant activity
We found that aromatic hydroxyl group facilitates hydrogen and electron abstraction by kynurenines, in agreement with experimental data and computations earlier performed for phenolic antioxidants
Summary
The kynurenine pathway (KP), the primary route of tryptophan degradation in mammalian cells, includes kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3HOK), 3-hydroxyanthranilic acid (3HAA), quinolinic acid (QUIN), and other metabolites collectively called kynurenines (Fig 1).There are multiple mechanisms of kynurenines’ action on nervous system. The kynurenine pathway (KP), the primary route of tryptophan degradation in mammalian cells, includes kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3HOK), 3-hydroxyanthranilic acid (3HAA), quinolinic acid (QUIN), and other metabolites collectively called kynurenines (Fig 1). The autoxidation of 3HOK and 3HAA leads to the hyperproduction of reactive oxygen species (ROS) which damage cellular lipids, proteins, and DNA [8,9,10]. Kynurenine 3-monooxygenase (KMO), an enzyme producing 3HOK from KYN, has been linked to the pathophysiology of HD by a mechanism involving ROS [11]. Accumulation of 3HOK in the central nervous system of Drosophila cardinal mutant leads to the progressive memory loss [12]. Since 3HOK is capable of auto-condensation, the eyes of this mutant, as well as the color of mammalian lens cataract [13] progressively get brown on ageing. The Drosophila eye color mutants are started to be envisioned as a therapeutic tools for HD [14]
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