Abstract
Kynurenines, the products of tryptophan oxidative degradation, are involved in multiple neuropathologies, such as Huntington's chorea, Parkinson's disease, senile dementia, etc. The major cause for hydroxykynurenines's neurotoxicity is the oxidative stress induced by the reactive oxygen species (ROS), the by-products of L-3-hydroxykynurenine (L-3HOK) and 3-hydroxyanthranilic acid (3HAA) oxidative self-dimerization. 2-aminophenol (2AP), a structural precursor of L-3HOK and 3HAA, undergoes the oxidative conjugation to form 2-aminophenoxazinone. There are several modes of 2AP dimerization, including both enzymatic and non-enzymatic stages. In this study, the free energies for 2AP, L-3HOK and 3HAA dimerization stages have been calculated at B3LYP/6-311G(d,p)//6-311+(O)+G(d) level, both in the gas phase and in heptane or water solution. For the intermediates, ionization potentials and electron affinities were calculated, as well as free energy and kinetics of molecular oxygen interaction with several non-enzymatically formed dimers. H-atom donating power of the intermediates increases upon the progress of the oxidation, making possible generation of hydroperoxyl radical or hydrogen peroxide from O2 at the last stages. Among the dimerization intermediates, 2-aminophenoxazinole derivatives have the lowest ionization potential and can reduce O2 to superoxide anion. The rate for O-H homolytic bond dissociation is significantly higher than that for C-H bond in non-enzymatic quinoneimine conjugate. However, the last reaction passes irreversibly, reducing O2 to hydroperoxyl radical. The inorganic ferrous iron and the heme group of Drosophila phenoxazinone synthase significantly reduce the energy cost of 2AP H-atom abstraction by O2. We have also shown experimentally that total antioxidant capacity decreases in Drosophila mutant cardinal with L-3HOK excess relative to the wild type Canton-S, and lipid peroxidation decreases in aged cardinal. Taken together, our data supports the conception of hydroxykynurenines' dual role in neurotoxicity: serving as antioxidants themselves, blocking lipid peroxidation by H-atom donation, they also can easily generate ROS upon dimerization, leading to the oxidative stress development.
Highlights
The kynurenine pathway (KP) is a primary route of tryptophan degradation in mammals
Computational study of the dimerization process may reveal the stages and intermediates being the source of the reactive oxygen species
We have modeled oxidative conjugation of kynurenines using quantum-chemical approaches, performing calculations for the energies of the dimerization stages, as well as the redox properties of the intermediates
Summary
The kynurenine pathway (KP) is a primary route of tryptophan degradation in mammals. Collectively called kynurenines, possess diverse neuroactive properties, being involved in the development of numerous neuropathologies, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), etc. Indoleamine-2,3-dioxygenase (IDO) or tryptophan-2,3-dioxygenase (TDO) governs the initial rate-limiting stage of KP, converting tryptophan to N-formylkynurenine, which is non-enzymatically hydrolyzed to kynurenine. Till the late 1970th, NAD+ synthesis was thought to be the only biological role for KP, its neuro- and immunomodulatory role is well-established [5]. Kynurenines are deeply involved in neurotoxicity, neuroinflammation and excitotoxicity. These three phenomena result from interrelationship of metabolic disturbances leading to increase in reactive oxygen and nitrogen species (ROS, RNS) [6]
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