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

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*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

40 Downloads (Pure)

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.

Original languageEnglish
JournalScientific Reports
Volume10
Pages (from-to)21574
Number of pages12
ISSN2045-2322
DOIs
Publication statusPublished - Dec 2020

Fingerprint

Dive into the research topics of 'Fine-tuning of lysine side chain modulates the activity of histone lysine methyltransferases'. Together they form a unique fingerprint.

Cite this