Dehydroalanine Formation from GPx Inhibited by Methylmercury: A DFT Study

The enzyme Glutathione Peroxidase (GPx) plays an important role in biological systems reducing the toxic hydrogen peroxide (H₂O₂) to water, using cysteine (Cys) or selenocysteine (Sec) residues. GPx can be inhibited by MeHg, a potent neurotoxin, by the S/Se–HgMe bond formation. We have investigated in silico the dehydroalanine (Dha) formation as the product involved in the possible mechanism of GPx inhibition by MeHg. Cys and Sec bonded to MeHg were modeled at the ZORA- BLYP-D3(BJ)/TZ2P level of theory. In addition, the tellurocysteine (Tec) case was studied for completeness and comparison. Our results demonstrate that the oxidation of MeHg-Cys/Sec/Tec is kinetically more favorable for Tec than Sec and Cys (R–CH–CH₂–XHgMe + H₂O₂ --> R–CH–CH₂–X(O)HgMe + H₂O; X = S, Se, Te; R= (NH₂)(COOH); ΔE^ǂ= 13, 10, and 4 kcal/mol, respectively). Similarly, the intramolecular β-elimination energetics for the Dha formation is more favorable according to the trend S << Se < Te (R–CH–CH₂–X(O)HgMe --> R–C=CH₂ + MeHgXOH; X = S, Se, and Te; R= (NH₂)(COOH); ΔE^ǂ= 13, 4, and 2 kcal/mol; ΔE = 8, -5, and -9 kcal/mol, respectively). Finally, MeHg- lowers the elimination activation energies with respect to alkylated residues Me-Cys/Sec/Tec (ΔE^ǂ= 20, 12, and 11 kcal/mol). The role of Hg and of the different chalcogen atoms on the β-elimination reactions is thoroughly elucidated.