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Chembiochem. 2019 Jul 9. doi: 10.1002/cbic.201900359. [Epub ahead of print]

Lysine Ethylation by Histone Lysine Methyltransferases.

Author information

1
Radboud Universiteit, NETHERLANDS.
2
Rheinisch Westfalische Technische Hochschule Aachen Fakultat fur Mathematik Informatik und Naturwissenschaften, GERMANY.
3
Shandong Agricultural University, CHINA.
4
University of Tennessee, UNITED STATES.
5
Rheinisch-Westfalische Technische Hochschule Aachen, GERMANY.
6
University of Southern Denmark, Department of Physics, Chemistry and Pharmacy, Campusvej 55, 5230, Odense, DENMARK.

Abstract

Biomedicinally important histone lysine methyltransferases (KMTs) catalyze the transfer of methyl group from S-adenosylmethionine (AdoMet) cosubstrate to lysine residues in histones and other proteins. Here we report experimental and computational investigations on human KMT-catalyzed ethylation of histone peptides using S-adenosylethionine (AdoEth) and Se-adenosylselenoethionine (AdoSeEth) cosubstrates. MALDI-TOF MS experiments revealed that, unlike monomethyltransferases SETD7 and SETD8, methyltransferases G9a and GLP do have a 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 (QM/MM) potential supported the experimental findings by providing an insight into the geometry and energetics of the enzymatic methyl/ethyl transfer process.

KEYWORDS:

enzyme catalysis; epigenetics; ethylation; histone; lysine

PMID:
31287209
DOI:
10.1002/cbic.201900359

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