Selenolysine: A new tool for traceless isopeptide bond formation

Despite their biological importance, post-translationally modified proteins are notoriously difficult to produce in a homogeneous fashion using conventional expression systems. Chemical protein synthesis or semi-synthesis offers a solution to this problem; however, traditional strategies often rely on sulfur-based chemistry that is incompatible with the presence of multiple cysteine residues in the target protein. To overcome these limitations, we present the design and synthesis of γ-selenolysine, a selenol-containing form of the commonly modified proteinogenic amino acid, lysine. The utility of γ-selenolysine is demonstrated with the traceless ligation of the small ubiquitin-like modifier protein, SUMO-1, to a peptide fragment of human glucokinase. The resulting polypeptide is poised for native chemical ligation in the presence of unprotected cysteine residues, demonstrating selenolysine’s potential in dual isopeptide/native chemical ligation strategies.