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 by using conventional expression systems. Chemical protein synthesis or semisynthesis offers a solution to this problem; however, traditional strategies often rel...

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Bibliographic Details
Published in:Chemistry : a European journal 2020-04, Vol.26 (22), p.4952-4957
Main Authors: Dardashti, Rebecca Notis, Kumar, Shailesh, Sternisha, Shawn M., Reddy, Post Sai, Miller, Brian G., Metanis, Norman
Format: Article
Language:English
Subjects:
Amino Acids
chemical protein synthesis
Chemical synthesis
Chemistry
Cysteine
Cysteine - chemistry
deselenization
expressed protein ligation
Glucokinase
Humans
Lysine
Lysine - chemistry
Peptides
Peptides - chemistry
Polypeptides
post-translational modification
Protein biosynthesis
Protein Processing, Post-Translational
Protein synthesis
Proteins
Residues
Selenium Compounds - chemistry
Semisynthesis
Sulfur
Sulfur - chemistry
SUMO-1 Protein - chemistry
SUMO-1 Protein - metabolism
SUMOylation
Synthetic peptides
Ubiquitin
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Summary:Despite their biological importance, post‐translationally modified proteins are notoriously difficult to produce in a homogeneous fashion by using conventional expression systems. Chemical protein synthesis or semisynthesis offers a solution to this problem; however, traditional strategies often rely on sulfur‐based chemistry that is incompatible with the presence of any 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 segment of human glucokinase. The resulting polypeptide is poised for native chemical ligation and chemoselective deselenization in the presence of unprotected cysteine residues. Selenolysine's straightforward synthesis and incorporation into synthetic peptides marks it as a universal handle for conjugating any ubiquitin‐like modifying protein to its target. The design and synthesis of γ‐selenolysine, a selenol‐containing form of the commonly modified proteinogenic amino acid, lysine is reported. The utility of γ‐selenolysine is demonstrated with the traceless ligation of the small ubiquitin‐like modifier protein, SUMO‐1, to a peptide segment of human glucokinase.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.202000310