Feasibility of the reaction between (R)-3-hydroxybutyrate & hydroxyl radicals

Energetic particles and secondary radiation encountered by astronauts during space flight result in the formation of a range of reactive oxygen species, including hydroxyl radicals (HO˙), which can lead to premature cell death. Several strategies have been proposed to combat the intracellular effects of radiation including use of exogeneous antioxidants. We have investigated the reaction between the major ketone body (R)-3-hydroxybutyrate (HB^-) and HO˙ at the SMD/M062X/6-311++G(d,p) level of theory. This revealed a bimolecular rate constant of 6.20 × 10⁹ dm³ mol^-1 s^-1 with hydrogen atom abstraction at the hydroxyalkyl C-H bond constituting the predominate reaction channel (Γ ≈ 30%). Proton coupled electron transfer between the hydroxyl group and HO˙ was thermodynamically and kinetically the least favourable (k = 8.20 × 10⁷ dm³ mol^-1 s^-1, Γ ≈ 1.3%) but produced an oxygen-centred radical exhibiting SOMO-HOMO inversion. Hydrogen abstraction at the methylene (k ≈ 1 × 10⁹ dm³ mol^-1 s^-1, Γ ≈ 20%) and methyl (k ≈ 6 × 10⁸ dm³ mol^-1 s^-1, Γ ≈ 10%) sites was of intermediate reactivity. Our estimates show that in dietary ketosis the half-life of HO˙ is shorter on reaction with HB^- than ascorbate (t_½ = 3.73 × 10^-8vs. 4.81 × 10^-7 s) suggesting that this is a viable approach for reducing the cellular impact of ionising radiation.