Novel N(Epsilon)-Acetyl-Lysine Analogs: Synthesis and Application

Protein posttranslational reversible lysine N^ε-acetylation and deacetylation have been recognized as an emerging intracellular signaling mechanism that plays critical roles in regulating gene transcription, cell-cycle progression, apoptosis, DNA repair, and cytoskeletal organization. Acetyltransferase-catalyzed creation, deacetylase-catalyzed destruction, and bromodomain-mediated specific recognition of N^ε-acetyl-lysine on proteins define the central events of this signaling mechanism. Due to the fact that N^ε-acetyl-lysine serves as the key recognition motif of this signaling mechanism, its analogs may help develop novel chemical modulating strategies and modulators that could provide potential therapeutics and chemical tools for a molecular dissection of this signaling mechanism.

In this study, i) the first non-hydrolyzable (or intracellular protein deacetylase-resistant) functional surrogate, i.e. N^ε-methanesulfonyl-lysine, for N^ε-acetyl-lysine regarding bromodomain binding interaction was developed. The availability of this non-hydrolyzable analog will promote the development of novel inhibitors of bromodomain/N^ε-acetyl-lysine recognition suitable for cellular studies; ii) deacetylase enzymes have been targeted for developing novel therapies of metabolic and age-related diseases and cancer, substrate recognition of sirtuin family of deacetylase enzymes was examined by using N^ε-acetyl-lysine analogs; iii) the binding interaction between bromodomain and lysine N^ε-acetylated target motifs was also evaluated.