Molecular basis of thiol oxidation by peroxides: aqueous solution and peroxiredoxins

ARI ZEIDA; ANÍBAL M. REYES; MARIANO CAMILO GONZÁLEZ LEBRERO; RAFAEL RADI; MADIA TRUJILLO; DARIO A. ESTRIN

Girona

Conferencia; Gordon Research Conference: Thiol-Based Redox Regulation & Signaling; 2014

GRC

Oxidation of cellular thiols containing compounds (such as free cysteine (Cys), glutathion or Cys residues in proteins), by reactive oxygen species, is a key event in a great variety of biological processes. In particular, the oxidation of thiols by H2O2 and/or peroxynitrite has been extensively studied, but besides great advances, the molecular reaction mechanism remains poorly understood. Furthermore, rate constants of this reaction for peroxidatic thiols in Cys-dependent peroxidases such as peroxiredoxins (Prxs), are several orders of magnitude larger than those observed for low molecular weight thiols (LMW). The first step of the process involves thiolate oxidation to sulfenic acid: RS + R ́OOH → RSOH + R ́OH We present an integrated combination of fast kinetics and hybrid quantum-classic molecular dynamics simulations, to explore this two- electron oxidation, comparing LMW thiols in aqueous solution and fast reacting thiols such as peroxidatic-Cys in Prxs, with both hydroperoxides.Free Cys[3,4] and MtAhpE[5], the one-Cys Prx from Mycobacterium tuberculosis, were used as models of LMW thiols and a Prx system,respectively. This integrated scheme allow us to get atomistic detailed information about the reaction mechanisms, showing that they are somehow different for each peroxide, and highlighting the importance of the environment surrounding the reactive thiol.