Design and synthesis of peptide-MCA substrates for a novel assay of histone methyltransferases and their inhibitors.
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.
Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Wakamatsu, Kitakyushu 808-0196, Japan.
Hongfang
H
Chi
Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan.
Yasushi
Y
Takemoto
Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Wakamatsu, Kitakyushu 808-0196, Japan.
Tienabe K
TK
Nsiama
Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Wakamatsu, Kitakyushu 808-0196, Japan. Electronic address: tmkato@life.kyutech.ac.jp.
Tamaki
T
Kato
Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Wakamatsu, Kitakyushu 808-0196, Japan.
Norikazu
N
Nishino
Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan.
Akihiro
A
Ito
Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Saitama 351-0198, Japan.
Minoru
M
Yoshida
D000595:Amino Acid Sequence; D003374:Coumarins / Q000737:chemistry*; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008745:Methylation; D010455:Peptides / Q000737:chemistry*; D013379:Substrate Specificity; D014158:Transcription, Genetic / Q000187:drug effects
C502573:4-methyl-coumaryl-7-amide; D003374:Coumarins; D004791:Enzyme Inhibitors; D010455:Peptides; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase
4-Methylcoumaryl-7-amides; Histone methyltransferase inhibitors; Histone methyltransferases; Peptide-MCA substrates