Fig 1.
Kynurenine pathway of tryptophan methabolism.
The implication of KP in a variety of physiological and pathophysiological processes, including anti-microbial and anti-tumor defense, neuropathology, immunoregulation, and antioxidant activity, has been ever drawing attention to biochemical properties of kynurenines [1]. Kynurenines are considered to be involved in ageing and numerous neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), etc. [2–4].
Table 1.
Hydrogen donating ability of kynurenines and phenolic antioxidants (levels II-III, III(LC-BLYP)).
Fig 2.
The highest occupied molecular orbitals (HOMOs) of kynurenines and phenolic antioxidants.
Color scheme, atoms: H–white, C–grey, O–red, N–blue. Isosurface value: 0.05. The lowest unoccupied molecular orbital (LUMO) has multiple nodes in the bonding region, mainly localized outside of the OH group (S1 Fig). For the ionized compounds, LUMO is moved from the charged group to the aromatic system; for L-3HOKNH3+, its form is nearly the same as that of L-3HOK HOMO. The geometry of HOMOs closely resembles the geometry of spin-orbits of cation radicals (S2 Fig). Hence HOMO correctly reproduces the geometry of the electron density in phenolic cations calculated at the DFT level. The main differences are between anion HOMOs and the corresponding spin-orbits after electron abstraction: spin-orbit is localized mainly on aromatic atoms and partly on α-carboxylic group. Spin-orbit of radicals after H-atom abstraction is localized on O*-atom and π-conjugated moiety, including the aromatic system and unsaturated side chains (S3 Fig). Delocalization is low in L-KYN, KYNAENOL, and phenol radicals. This may explain their lower capability to donate H compared with hydroxykynurenines and substituted phenols.
Fig 3.
BDE, IP, and k(T) values of kynurenines in the gas phase and water solution.
(a) BDE values. (b) IP values. (c) k(T) values (in logarithmic form). Blue–the gas phase, red–water solution. BDE (IV) rankings for H-atom in the gas phase are nearly the same as for BDE/BDECOR (II, III). BDE is abnormally high for two symmetric compounds, phenol and DTBP. DTBA have much lower BDE, which is in agreement with its high antioxidant power. BDE for DIBP and DIBA are close to those for DTBA and, presumably, the true BDE value for DTBP. For the uncharged kynurenines with the OH group, BDE is maximal for KYNAENOL and minimal for DXAN, both in the gas phase and in water solution. XAA and KYNA have smaller BDE in oxo form than in enol form.
Table 2.
Hydrogen and electron donating abilities of kynurenines and phenolic antioxidants in the gas phase and water solution.
Table 3.
Thermodynamic and kynetic parameters of kynurenines H-atom donation to phenoxyl radical and methyl peroxy radical.
Fig 4.
Antioxidants in compex with phenoxyl radical (Ph-O*) and methyl peroxy radical (Met-OO*).
Abbreviations: Ant–antioxidant, Ant*–antioxidant radical, SP–saddle point structure. Color scheme, atoms: H–white, C–cyan, O–red, N–blue; color scheme, antioxidants in complex with radicals: 3HAA–red, L-3HOK–orange, XAAOXO−grey, XAAENOL−green, XAAOXO/CO2- –purple, DTBP–blue, DTBA–cyan.
Table 4.
Geometry of antioxidant in complex with radicals.
Fig 5.
SOMOs and spin-orbits of kynyrenine-radical TSs.
Color scheme, atoms: H–white, C–cyan, O–red, N–blue. Isosurface values: 0.05 –for SOMOs, 0.005 –for spin-orbits.
Table 5.
ESOMO (kcal/mol), charges, and spin densities (e) for the transition structures of kynurenines in complex with free radicals.
Fig 6.
Products of Met-OO* addition to the aromatic ring of antioxidants.
Color scheme, atoms: H–white, C–cyan, O–red, N–blue; color scheme, the products of Met-OO* addition to antioxidant radicals: 3HAA–red, L-3HOK–orange, XAAOXO−grey, XAAENOL−green, XAAOXO/CO2- –purple, DTBP–blue.
Table 6.
Thermodynamic parameters (kcal/mol) of methyl peroxy radical addition to the aromatic ring of kynurenines radicals.
Table 7.
Antioxidants lipophilicity.