Аннотация: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.