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Enzymatic Mechanism and Product Specificity of SET-Domain Protein Lysine Methyltransferases

Xiaodong Zhang and Thomas C. Bruice
Proceedings of the National Academy of Sciences of the United States of America
Vol. 105, No. 15 (Apr. 15, 2008), pp. 5728-5732
Stable URL: http://www.jstor.org/stable/25461677
Page Count: 5
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Enzymatic Mechanism and Product Specificity of SET-Domain Protein Lysine Methyltransferases
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Abstract

Molecular dynamics and hybrid quantum mechanics/molecular mechanics have been used to investigate the mechanisms of ⁺AdoMet methylation of protein-Lys-NH₂ catalyzed by the lysine methyltransferase enzymes: histone lysine monomethyltransferase SET7/9, Rubisco large-subunit dimethyltransferase, viral histone lysine trimethyltransferase, and the Tyr245Phe mutation of SET7/9. At neutrality in aqueous solution, primary amines are protonated. The enzyme reacts with Lys-NH₃⁺ and ⁺AdoMet species to provide an Enz·Lys-NH₃⁺·⁺AdoMet complex. The close positioning of two positive charges lowers the pKₐ of the Lys-NH₃⁺ entity, a water channel appears, and the proton escapes to the aqueous solvent; then the reaction Enz·Lys-NH₂·⁺AdoMet → Enz·Lys-N(Me)H₂⁺·AdoHcy occurs. Repeat of the sequence provides dimethylated lysine, and another repeat yields a trimethylated lysine. The sequence is halted at monomethylation when the conformation of the Enz·Lys-N(Me)H₂⁺·⁺AdoMet has the methyl positioned to block formation of a water channel. The sequence of reactions stops at dimethylation if the conformation of Enz·Lys-N(Me)₂H⁺+·⁺AdoMet has a methyl in position, which forbids the formation of the water channel.

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