Fine-tuning of lysine side chain modulates the activity of histone lysine methyltransferases

• Main Authors: Abbas H. K. Al Temimi, Jona Merx, Christian J. van Noortwijk, Giordano Proietti, Romano Buijs, Paul B. White, Floris P. J. T. Rutjes, Thomas J. Boltje, Jasmin Mecinović
• Format: Article
• Language: English
• Published: Nature Publishing Group 2020-12-01
• Series: Scientific Reports
• Online Access: https://doi.org/10.1038/s41598-020-78331-0

Abstract Histone lysine methyltransferases (KMTs) play an important role in epigenetic gene regulation and have emerged as promising targets for drug discovery. However, the scope and limitation of KMT catalysis on substrates possessing substituted lysine side chains remain insufficiently explored. Here, we identify new unnatural lysine analogues as substrates for human methyltransferases SETD7, SETD8, G9a and GLP. Two synthetic amino acids that possess a subtle modification on the lysine side chain, namely oxygen at the γ position (KO, oxalysine) and nitrogen at the γ position (KN, azalysine) were incorporated into histone peptides and tested as KMTs substrates. Our results demonstrate that these lysine analogues are mono-, di-, and trimethylated to a different extent by trimethyltransferases G9a and GLP. In contrast to monomethyltransferase SETD7, SETD8 exhibits high specificity for both lysine analogues. These findings are important to understand the substrate scope of KMTs and to develop new chemical probes for biomedical applications.