ABSTRACT
Methylation of lysine residues in histone proteins is catalyzed by S-adenosylmethionine (SAM)-dependent histone lysine methyltransferases (KMTs), a genuinely important class of epigenetic enzymes of biomedical interest. Here we report synthetic, mass spectrometric, NMR spectroscopic and quantum mechanical/molecular mechanical (QM/MM) molecular dynamics studies on KMT-catalyzed methylation of histone peptides that contain lysine and its sterically demanding analogs. Our synergistic experimental and computational work demonstrates that human KMTs have a capacity to catalyze methylation of slightly bulkier lysine analogs, but lack the activity for analogs that possess larger aromatic side chains. Overall, this study provides an important chemical insight into molecular requirements that contribute to efficient KMT catalysis and expands the substrate scope of KMT-catalyzed methylation reactions.
Subject(s)
Histone-Lysine N-Methyltransferase/chemistry , Lysine/chemistry , Catalysis , Catalytic Domain , HumansABSTRACT
Histone lysine methyltransferases (KMTs) are biomedicinally important class of epigenetic enzymes that catalyse methylation of lysine residues in histones and other proteins. Enzymatic and computational studies on the simplest lysine analogues that possess a modified main chain demonstrate that the lysine's backbone contributes significantly to functional KMT binding and catalysis.
