Abstract
Histone lysine methyltransferases (KMTs) are biomedically important epigenetic enzymes that catalyze the transfer of methyl group from S-adenosylmethionine to lysine’s nucleophilic ε-amino group in histone tails and core histones. Understanding the chemical basis of KMT catalysis is important for discerning its complex biology in disease, structure-function relationship, and for designing specific inhibitors with therapeutic potential. Here we examine histone peptides, which possess simplest lysine analogs with different nucleophilic character, as substrates for human KMTs. Combined MALDI-TOF MS experiments, NMR analyses and molecular dynamics and free-energy simulations based on quantum mechanics/molecular mechanics (QM/MM) potential provide experimental and theoretical evidence that KMTs do have an ability to catalyze methylation of primary amine-containing N-nucleophiles, but do not methylate related amide/guanidine-containing N-nucleophiles as well as simple O- and C-nucleophiles. The results demonstrate a broader, but still limited, substrate scope for KMT catalysis, and contribute to rational design of selective epigenetic inhibitors.
Highlights
Histone lysine methyltransferases (KMTs) are biomedically important epigenetic enzymes that catalyze the transfer of methyl group from S-adenosylmethionine to lysine’s nucleophilic ε-amino group in histone tails and core histones
Our recent studies demonstrated that the L-stereochemistry, the chain length, and the main chain all determine a degree of KMT-catalyzed methylation, highlighting that lysine possesses the optimal L-configuration and the length of side chain for efficient KMTcatalyzed methylation[24,25,26,27]
Despite ongoing examinations of basic biomolecular requirements that define the activity of numerous enzymes, an indepth understanding of the underlying chemical mechanisms that control the enzymatic methylation of lysine and other residues remains incomplete
Summary
Histone lysine methyltransferases (KMTs) are biomedically important epigenetic enzymes that catalyze the transfer of methyl group from S-adenosylmethionine to lysine’s nucleophilic ε-amino group in histone tails and core histones. Examinations of sterically demanding SAM analogs as cosubstrates for recombinantly expressed KMTs, and in cellular assays showed that KMTs catalyze the methylation reaction, and related alkylation reactions[21,22,23]. At present, it is still unknown whether KMTs do have an ability to catalyze methylation of lysine analogs that possess nucleophilic groups other than the Nε amino group. We report integrated experimental and computational studies on human KMTcatalyzed methylation of the simplest lysine analogs that possess a NH2
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