Maneb adducts human peroxiredoxin 3 through thiol interactions

Abstract

The dithiocarbamate fungicide maneb (MB) has garnered increasing concern due to its association with Parkinson's disease (PD) and the overall negative human health effects of pesticides in agriculture. As one of several environmental toxicant models of PD, MB has been shown to induce global dehydrogenase inhibition, mitochondrial dysfunction, proteostasis disruption, and delayed cell death in neuronal in vitro models. Recently, our group has reported distinct alterations in bioenergetics and energy metabolism after an acute exposure of MB to neuroblastoma cells. Additionally, this acute MB exposure in neuroblastoma also caused a disruption in peroxiredoxin 3 (Prdx3) oxidation, uncovering significant protein thiol interactions. In the current study, human recombinant Prdx3 was evaluated to evaluate direct thiol-thiol interactions between MB and Prdx3 protein. We report a direct, concentration dependent modification of Prdx3 after MB exposure in our system. Further investigation revealed that MB directly adducts Prdx3 protein through disulfide chemistry, similar to the hyperoxidation or glutathionylation of critical cysteine residues. Computational simulations confirm the disulfide bonding on both reduced monomers and oxidized dimers of Prdx3 protein by a possible MB polymer. The data presented strengthens the argument that MB can preferentially target thiol regulatory switches present in many proteins, giving further credence to the MB model of PD in which many disease-associated proteins contain these functional groups, e.g. ubiquinol-cytochrome c reductase, aconitase, and aldehyde dehydrogenase (ALDH2). Furthermore, MB's ability to mimic hyperoxidation of Prdx3 protein introduces a novel dynamic of toxicity within the toxicant model that accounts for the oxidative distress that cannot be reversed by therapeutic anti-oxidants in PD.