Metmyoglobin Reduction via Sulfides and Disulfides Interplay: A trans -S-Sulfuration Mechanism

In this work, we investigate on the metal-centered autocatalytic reduction of metmyoglobin (MbFeIII(H2O)) by sulfide species (H2S/HS–), focusing on the role of hydrodisulfide (HSS–) as the autocatalytic species in the reaction mechanism. The reaction is initiated with the formation of the MbFeIII(SH–) complex, under inert atmosphere. By adding increasing concentrations of HSS– to MbFeIII(SH–) complex, an acceleration of the metal-centered reduction forming myoglobin (MbFeII) is observed. Furthermore, the addition of HSS– to MbFeIII(SH–) modifies the autocatalytic kinetic regime suggesting an interplay between the bound and added sulfur species. Spin-trapping experiments that arrest the autocatalytic regime still yield the MbFeII product in the presence of added HSS–, enabling the isolated kinetic analysis of the disulfides-mediated reduction of MbFeIII(SH–). QM/MM calculations allowed a description of mechanistic details, suggesting that the most plausible mechanism for the autocatalytic step consists in a trans-S-sulfuration reaction where, while the Fe–S bond remains intact, a sulfur atom from the HSS– anion binds the coordinated sulfide in MbFeIII(SH–). Altogether, this study supports a metal-centered reduction mechanism based on a new S–S bond formation for the reaction intermediate, and provides a framework for hemeprotein reduction by the interplay of sulfide and disulfide species.