Design and synthesis of peptide-MCA substrates for a novel assay of histone methyltransferases and their inhibitors.

Hongfang Chi, Yasushi Takemoto, Tienabe K Nsiama, Tamaki Kato, Norikazu Nishino, Akihiro Ito, Minoru Yoshida

Bioorganic & medicinal chemistry 2014 Feb 15

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Histone methyltransferases (HMTs) play an important role in controlling gene expression through site-specific methylation of lysines in core and linker histones within chromatin. As the typical HMTs, G9a and Set7/9 have been intensively studied that G9a is specific to the methylation at H3K9 and H3K27 and represses transcription, while Set7/9 methylates at H3K4. In this report we prepared various peptide-MCAs (4-methylcoumaryl-7-amides) related to histone tail and protein-substrates such as p53 and estrogen receptor-α. The fluorogenic substrates are applied for the assay of HMTs and an inhibitor, for example. The most sensitive and specific MCA-substrates to G9a and Set7/9 are discovered. The peptide-MCAs corresponding to the methylation sequences are promising for screening of HMT inhibitors. Copyright © 2014 Elsevier Ltd. All rights reserved.

Citation

Hongfang Chi, Yasushi Takemoto, Tienabe K Nsiama, Tamaki Kato, Norikazu Nishino, Akihiro Ito, Minoru Yoshida. Design and synthesis of peptide-MCA substrates for a novel assay of histone methyltransferases and their inhibitors. Bioorganic & medicinal chemistry. 2014 Feb 15;22(4):1268-75