Oxidative cyclization reagents reveal tryptophan cation-π interactions.

Area of Science:

• Biochemistry
• Chemical Biology
• Proteomics

Background:

• Selective covalent modification of amino acids is crucial for protein studies.
• Cysteine and lysine are typically targeted due to their reactivity.
• Tryptophan, a rare amino acid, remains challenging to modify selectively.

Purpose of the Study:

• To develop a novel redox-based strategy for selective tryptophan bioconjugation.
• To enable efficient and specific labeling of tryptophan residues on peptides and proteins.
• To profile hyper-reactive tryptophan sites and their functional roles in proteomes.

Main Methods:

• Utilized oxaziridine reagents mimicking natural oxidative cyclization reactions.
• Developed a method termed tryptophan chemical ligation by cyclization (Trp-CLiC).
• Applied Trp-CLiC for selective payload attachment to tryptophan residues.

Main Results:

• Achieved highly efficient and specific tryptophan labeling comparable to click reactions.
• Enabled global profiling of hyper-reactive tryptophan sites across entire proteomes.
• Identified tryptophan residues involved in cation-π interactions and protein phase separation.

Conclusions:

• Trp-CLiC provides a powerful new tool for chemical biology and proteomics.
• The method allows for precise manipulation and study of tryptophan residues.
• This approach offers insights into protein function, particularly cation-π interactions and phase separation.