Lysine Ethylation by Histone Lysine Methyltransferases |
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| Authors: | Abbas H. K. Al Temimi Dr. Michael Martin Dr. Qingxi Meng Danny C. Lenstra Dr. Ping Qian Prof. Dr. Hong Guo Prof. Dr. Elmar Weinhold Prof. Dr. Jasmin Mecinović |
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| Affiliation: | 1. Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands;2. Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056 Aachen, Germany;3. Chemistry and Material Science Faculty, Shandong Agricultural University, Daizong Road No.61, Tai'an, 271018 P.R. China;4. Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, 1311 Cumberland Avenue, Knoxville, TN, 37996 USA |
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| Abstract: | Biomedicinally important histone lysine methyltransferases (KMTs) catalyze the transfer of a methyl group from S-adenosylmethionine (AdoMet) cosubstrate to lysine residues in histones and other proteins. Herein, experimental and computational investigations on human KMT-catalyzed ethylation of histone peptides by using S-adenosylethionine (AdoEth) and Se-adenosylselenoethionine (AdoSeEth) cosubstrates are reported. MALDI-TOF MS experiments reveal that, unlike monomethyltransferases SETD7 and SETD8, methyltransferases G9a and G9a-like protein (GLP) do have the capacity to ethylate lysine residues in histone peptides, and that cosubstrates follow the efficiency trend AdoMet>AdoSeEth>AdoEth. G9a and GLP can also catalyze AdoSeEth-mediated ethylation of ornithine and produce histone peptides bearing lysine residues with different alkyl groups, such as H3K9meet and H3K9me2et. Molecular dynamics and free energy simulations based on quantum mechanics/molecular mechanics potential supported the experimental findings by providing an insight into the geometry and energetics of the enzymatic methyl/ethyl transfer process. |
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| Keywords: | epigenetics enzymes histones molecular dynamics transferases |
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