Chiral Posttranslational Modification to Lysine ε-Amino Groups.

Area of Science:

• Biochemistry and Molecular Biology
• Proteomics and Posttranslational Modifications
• Metabolic Regulation

Background:

• Proteomic analysis reveals diverse acyl modifications on protein lysine residues, impacting cellular processes.
• While lysine acetylation is well-studied, other acyl PTMs, especially chiral ones, remain less understood.
• Lysine deacylases, including histone deacetylases (HDACs) and sirtuins (SIRTs), play critical roles in reversing these modifications.

Purpose of the Study:

• To investigate the biological significance of chiral lysine posttranslational modifications (PTMs).
• To explore the distinct metabolic origins and enzymatic regulation of stereoisomers of lysine acylation.
• To highlight the importance of distinguishing between individual stereoisomers of PTMs.

Main Methods:

• Development of selective inhibitors and molecular probes for lysine deacylase enzymes (HDACs and SIRTs).
• Analysis of acyl substrate scope using chemically synthesized peptide substrates.
• Utilizing photo-cross-linking probes to study enzyme-substrate interactions.

Main Results:

• Identified chiral PTMs like ε-N-β-hydroxybutyryllysine (Kbhb) and ε-N-lactyllysine (Kla) with distinct stereoisomers.
• Demonstrated that different stereoisomers of Kbhb and Kla arise from distinct metabolic pathways and are regulated differently by eraser enzymes (HDACs).
• Showcased that chiral lysine modifications influence gene transcription and metabolic enzyme activity.

Conclusions:

• Chiral lysine PTMs represent a critical layer of biological regulation with stereoisomer-specific functions.
• Understanding the distinct origins and enzymatic processing of PTM stereoisomers is essential for deciphering their roles in health and disease.
• Further research is needed to fully elucidate the biological impact of these chiral modifications.