Insights into the catalytic mechanism of synthetic glutathione peroxidase mimetics

Abstract

Glutathione Peroxidase (GPx) is a key selenoenzyme that protects biomolecules from oxidative damage. Extensive research has been carried out to design and synthesize small organoselenium compounds as functional mimics of GPx. While the catalytic mechanism of the native enzyme itself is poorly understood, the synthetic mimics follow different catalytic pathways depending upon the structures and reactivities of various intermediates formed in the catalytic cycle. The steric as well as electronic environments around the selenium atom not only modulate the reactivity of these synthetic mimics towards peroxides and thiols, but also the catalytic mechanisms. The catalytic cycle of small GPx mimics is also dependent on the nature of peroxides and thiols used in the study. In this review, we discuss how the catalytic mechanism varies with the substituents attached to the selenium atom.

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

“…Small molecule mimetics of glutathione peroxidases (GPx) were used as tools to remove both aliphatic and aromatic hydroperoxides and protect the cells from oxidative insults. 359 To selectively remove and probe the role of mitochondrial hydroperoxides, the GPx mimetic, ebselen, was linked to the TPP + moiety. 360 Mito-Ebselen (Chart 53) was shown to bind to energized mitochondria and be reduced by mitochondrial glutathione, a prerequisite for its peroxidase-like activity.…”

In Silico Studies of Mammalian δ‐ALAD Interactions with Selenides and Selenoxides

“…The nucleophilic attack at the Cys124 forms a disulfide bridge (−S−S−) in δ‐ALAD. Similar interactions between Se and S have been described in glutathione peroxidase and thioredoxin reductase and other theoretical works with sulfhydryl‐ and/or selenohydryl‐containing proteins . In this study, the Se … S distances ranged from 3.88 to 4.75 Å (Table ) indicating a possible nucleophilic attack from the S atom of Cys124 in the Se atom in the selenides and selenoxides.…”

“…Similar interactions between Se and S have been described in glutathione peroxidase and thioredoxin reductase and other theoretical works with sulfhydryl-and/or selenohydryl-containing proteins. [32][33][34][35][36][37] In this study, the Se … S distances ranged from 3.88 to 4.75 Å ( Table 2) indicating a possible nucleophilic attack from the S atom of Cys124 in the Se atom in the selenides and selenoxides. In addition, the analysis of electrostatic potential map of the active site of d-ALAD ( Figure 6 and Table 3) confirmed the nucleophilic character of cysteinyl residues (negative charged regions around the S atom is depicted in red, Figure 6).…”

A novel nanozyme based on selenopeptide-modified gold nanoparticles with a tunable glutathione peroxidase activity

“…[28][29][30] Glutathione peroxidase (GPx) is an important selenoenzyme in the cellular antioxidant defense system, which protects cells from oxidative damage by catalyzing the degradation of a variety of hydroperoxides (ROOH) using glutathione (GSH) as the reductant. [31][32][33][34][35] GPx contains an essential selenocysteine (Sec) residue at its active site, [36][37][38] and this residue has clear catalytic characteristics. 39,40 Considerable effort has been invested in constructing various GPx mimics, 41,42 including small molecules, 43,44 peptides, 45 cyclodextrin derivatives, 46,47 abzymes, 48 bioimprinting proteins, 49,50 and nanozymes.…”