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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.
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Details
1 Institute for Molecules and Materials, Radboud University, Nijmegen, The Netherlands (GRID:grid.5590.9) (ISNI:0000000122931605)
2 Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense, Denmark (GRID:grid.10825.3e) (ISNI:0000 0001 0728 0170)
3 Institute for Molecules and Materials, Radboud University, Nijmegen, The Netherlands (GRID:grid.5590.9) (ISNI:0000000122931605); Department of Blood Transfusion, China-Japan Union Hospital, Jilin University, Changchun, P.R. China (GRID:grid.64924.3d) (ISNI:0000 0004 1760 5735)
4 Mercachem B.V., Nijmegen, The Netherlands (GRID:grid.64924.3d)
5 Chiralix B.V., Nijmegen, The Netherlands (GRID:grid.64924.3d)
6 Chemistry and Material Science Faculty, Shandong Agricultural University, Tai’an, P.R. China (GRID:grid.440622.6) (ISNI:0000 0000 9482 4676)
7 Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, USA (GRID:grid.411461.7) (ISNI:0000 0001 2315 1184)
8 Institute for Molecules and Materials, Radboud University, Nijmegen, The Netherlands (GRID:grid.5590.9) (ISNI:0000000122931605); Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense, Denmark (GRID:grid.10825.3e) (ISNI:0000 0001 0728 0170)