Protein Cross-Linking as a Mechanism of Cytotoxicity for Bifunctional Electrophiles
A variety of industrial chemicals, plant and microbial secondary metabolites, and oxidative stress byproducts contain electrophilic centers that are able to react with nucleophilic sites in proteins. These reactions yield potential cytotoxic consequences. The cytotoxicity of a panel of eight structurally diverse bifunctional electrophiles were compared to their monofunctional analogs in order to quantify the enhancement in toxicity afforded by molecules with two electrophilic centers. Results of liquid toxicity assays by growth inhibition in yeast cells show a marked increase in toxicity of bifunctional electrophiles over monofunctional analogs. The bifunctional molecules are up to 500 times more toxic than respective monofunctional analogs. Molecules bearing electrophilic centers that were preferentially reactive with thiol groups showed enhanced toxicity over those reactive with amine groups. Each of the bifunctional electrophiles is capable of cross-linking recombinant cytosolic thioredoxin (Trx2) from baker's yeast in vitro, forming protein aggregates. Taken together, our results show that bifunctional protein cross-linkers, while having two electrophilic centers would likely result in only a 2-fold enhancement of toxicity, exhibit considerably greater toxicity than simple protein alkylating agents.
© Copyright 2013 Nikolai Radzinski