Structure-Activity Correlation and Mechanistic Investigations of Glutathione Peroxidase-Like Catalytic Activity of Diaryl Diselenides

Abstract

Hydroperoxides are very harmful and they can oxidize several biomolecules, causing different disease states. Glutathione peroxidase (GPx) is a mammalian selenoenzyme which protects human body from oxidative damage by catalyzing the reduction of harmful peroxides using glutathione (GSH) as a cofactor. GPx contains selenocysteine in its active site. The catalytic cycle of GPx enzymes is believed to involve three steps. In the first step, the reduced selenolate moiety (E-SeH) of Sec residue reduces hydroperoxides to water (or alcohol) to form oxidized selenenic acid (E-SeOH), which upon reaction with one equivalent of GSH generates selenenyl sulfide (E-SeSG) intermediate. A second equivalent of cellular GSH attacks at the –Se-S-bond to regenerate the active selenol species with elimination of the oxidized GSH (GSSG) and thus completes the catalytic cycle (Scheme 1). Therefore, the formation of the selenol species from the selenenyl sulfide intermediate is a crucial step for the catalytic activity. Cleavage of the -Se-S-bond is the rate determining step in the overall process. The GSH concentration in the cellular level is maintained by an enzyme glutathione reductase