A novel tyrosine hyperoxidation enables selective peptide cleavage.

Area of Science:

• Chemical Biology
• Organic Chemistry
• Mass Spectrometry

Background:

• Selective peptide bond cleavage is crucial for peptide analysis and modification.
• Current methods often lack specificity or require harsh conditions.
• Tyrosine residues present unique challenges for selective chemical manipulation.

Purpose of the Study:

• To report a novel method for selective peptide cleavage via tyrosine hyperoxidation.
• To demonstrate the utility of this method for cyclic peptide sequencing.
• To explore the potential of the hyperoxidized tyrosine motif in bioconjugation and synthesis.

Main Methods:

• Utilized Dess-Martin periodinane for tyrosine hyperoxidation under mild conditions.
• Applied the oxidative cleavage to naturally occurring cyclic peptides, including depsipeptides and lipopeptides.
• Employed tandem mass spectrometry (MS/MS) for sequence determination of linearized peptides.

Main Results:

• Achieved selective scission of the N-terminal amide bond of tyrosine.
• Generated a unique hyperoxidized tyrosine motif (4,5,6,7-tetraoxo-1H-indole-2-carboxamide).
• Successfully sequenced three cyclic peptides, simplifying analysis compared to intact cyclic structures.
• Demonstrated broad substrate scope, including peptides with post-translational modifications.

Conclusions:

• The novel tyrosine hyperoxidation enables efficient and selective peptide cleavage.
• This method significantly simplifies cyclic peptide sequencing by MS/MS.
• The hyperoxidized tyrosine motif serves as a versatile electrophilic handle for peptide modification and bioconjugation.