The 2H+/2e- free radical scavenging mechanisms of uric acid: thermodynamics of N-H bond cleavage

Double (2H(+)2e(-)) free radical scavenging mechanisms of the most abundant endogenous plasma antioxidant uric acid were theoretically studied using DFT method M05-2X/6-311++G(d,p) coupled with SMD solvation model. Calculations were performed for double, two sequential 1H(+)/1e(-) hydrogen atom transfer (HAT), double electron transfer followed by proton transfer (ET-PT) and double sequential proton loss electron transfer (SPLET) mechanisms in water as a solvent. It was found that inactivation of the first free radical by uric acid (the first 1H(+)+/1e(-) mechanism) occurs at its 3-N site and inactivation of another one (the second 1H(+)+/1e(-) mechanism) occurs at 7-N site of uric acid 3-N-center dot radical. The final product of all studied 2H(+)/2e(-) pathways is uric acid quinonoid diimine. Obtained results point to the SPLET mechanism as the favorable free radical scavenging mechanism by uric acid. Taking into account electronic properties of scavenged free radicals, double HAT mechanism is found to be competitive to double SPLET mechanism. Second mechanisms are less energy demanding than the first ones indicating 2H(+)/2e(-) processes as plausible. On the basis of exergonicity of the calculated reaction free energies, the reactivity of uric acid toward free radicals was predicted to decrease as follows: HO center dot and Cl3COO center dot > alkoxyl, peroxyl >> superoxide radical. (C) 2015 Elsevier B.V. All rights reserved.