Selenoprotein active site (Sec-AS)

The selenoprotein active site is a specialized catalytic region characterized by the presence of selenocysteine (Sec), the 21st amino acid (UniProt, 2023). This site is found in a diverse family of approximately 25 human enzymes, including thioredoxin reductases (TrxR) and glutathione peroxidases (GPx), which are essential for maintaining cellular redox homeostasis and protecting against oxidative stress (PubMed, PMID: 29153831). The high nucleophilicity of the selenium atom in Sec makes these active sites exceptionally efficient at catalyzing redox reactions but also renders them highly susceptible to inhibition by electrophilic compounds and heavy metals like gold and arsenic (PubChem, 2024). In therapeutic contexts, targeting the selenoprotein active site—particularly in TrxR—is a strategy used to induce oxidative stress and apoptosis in cancer cells, which often overexpress these enzymes to survive high metabolic demands (PubMed, PMID: 24561143). However, because this site is a conserved structural motif across multiple essential proteins rather than a single unique target, achieving pharmacological selectivity remains a significant challenge (Nature Reviews Drug Discovery, 2018). Consequently, while it is a valid site for drug interaction, the term refers to a class of functional sites rather than a specific individual protein target.

Other names

Selenocysteine catalytic siteSec-containing active siteSelenocysteine residueSelenoprotein redox center

Covalent modification of the nucleophilic selenocysteine residue, leading to irreversible or reversible enzyme inhibition and disruption of cellular redox balance.