Synthesis and Evaluation of a Stable Isostere of Malonyllysine. (5th November 2021)

• Record Type: Journal Article
• Authors: Jing, Yihang; Bergholtz, Sarah E.; Omole, Anthony; Kulkarni, Rhushi A.; Zengeya, Thomas T.; Yoo, Euna; Meier, Jordan L.
• Is Part Of: Chembiochem. Volume 23:Number 1(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-11-05
• Subjects: acetylation -- isosteres -- malonylation -- post-translational modification -- unnatural amino acids; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.202100491
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: Lysine malonylation is a recently characterized post‐translational modification involved in the regulation of energy metabolism and gene expression. One unique feature of this post‐translational modification is its potential susceptibility to decarboxylation, which poses possible challenges to its study. As a step towards addressing these challenges, 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 acid's 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 and histone deacylases, 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 post‐translational modification, providing a foothold for tool development and functional analyses. Abstract : The thermal‐induced decarboxylation property of lysine malonylation may impose potential challenges to its study. Our study demonstrated that malonyltetrazole‐modified lysine outstands as a stable bioisostere of malonyllysine to address such challenges. Enzymology data also verified that malonyl and malonyltetrazole share similar molecular interaction surfaces for receptor recognition.