Abstract
Histone lysine methyltransferases (KMTs) represent an important class of epigenetic enzymes that play essential roles in regulation of gene expression in humans. Members of the KMT family catalyze the transfer of the methyl group from S-adenosylmethionine (SAM) to lysine residues in histone tails and core histones. Here we report combined MALDI-TOF MS experiments, NMR analyses and quantum mechanical/molecular dynamics studies on human KMT-catalyzed methylation of the most related shorter and longer lysine analogues, namely ornithine and homolysine, in model histone peptides. Our experimental work demonstrates that while lysine is an excellent natural substrate for KMTs, ornithine and homolysine are not. This study reveals that ornithine does not undergo KMT-catalyzed methylation reactions, whereas homolysine can be methylated by representative examples of human KMTs. The results demonstrate that the specificity of KMTs is highly sensitive to the side chain length of the residue to be methylated. The origin for the degree of the observed activities of KMTs on ornithine and homolysine is discussed.