Abstract
Lysine malonylation is a recently characterized posttranslational modification involved in the regulation of energy metabolism and gene expression. Two unique features of this posttranslational modification are its negative charge and potential susceptibility to decarboxylation, both of which pose possible challenges to its study. As a step towards addressing these challenges, here we report the synthesis and evaluation of a stable isostere of malonyllysine. First, we find that synthetic substitution of the malonyl group with a tetrazole isostere results in amino acids resistant to thermal decarboxylation. Next, we demonstrate that protected variants of this amino acid are readily incorporated into peptides. Finally, we show that tetrazole isosteres of malonyllysine can be recognized by anti-malonyllysine antibodies, validating their ability to mimic features of the endogenous lysine modification. Overall, this study establishes a new chemical strategy for stably mimicking a metabolite-derived posttranslational modification, providing a foothold for tool development and functional analyses.
Competing Interest Statement
The authors have declared no competing interest.
