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Kinetic Analysis of the Inhibition of the NSD1, NSD2 and SETD2 Protein Lysine Methyltransferases by a K36M Oncohistone Peptide
Author(s) -
Schuhmacher Maren,
Kusevic Denis,
Kudithipudi Srikanth,
Jeltsch Albert
Publication year - 2017
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201701940
Subject(s) - methyltransferase , histone h3 , lysine , methylation , peptide , enzyme , histone , histone methyltransferase , biochemistry , chemistry , microbiology and biotechnology , biology , amino acid , dna
Methylation of histone 3 (H3) at lysine K36 is catalyzed by the NSD1, NSD2 and SETD2 protein lysine methyltransferases (PKMTs). In cancers, somatic K36M mutations were observed and shown to inhibit NSD2 and SETD2. We conducted a comparative steady‐state kinetic analysis of the inhibition of all three H3 K36 specific PKMTs by an inhibitory H3 (27‐43) peptide containing the K36M oncomutation. Our data show that NSD1 is also inhibited by the K36M mutation. With all three enzymes, we observed that the inhibition constant K I is about 1.5 fold lower than the K M for the corresponding substrate peptide indicating a better binding of the inhibitory peptide. This numerical similarity suggests a related mechanism of inhibition in all three cases in agreement with the conserved architecture of the active sites of these enzymes. The mechanism of inhibition of PKMTs by target lysine to methionine mutations is discussed.