ヒストン脱メチラーゼLSD1のためのメカニズムベースの活性化剤である
Jeffrey C Culhane1, Lawrence M Szewczuk, Xin Liu
1Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Journal of the American Chemical Society
|April 6, 2006
まとめ
研究者らは,ヒストン脱メチラーゼLSD1 (ライシン特異脱メチラーゼ1) を標的とする選択的阻害剤,化合物1を開発した. このメカニズムベースの不活性化剤は,FADに結合し,ヒストンの改変とクロマチンの改変を研究するための新しいツールを提供します.
科学分野:
- バイオケミストリー バイオケミストリー
- 分子生物学は分子生物学である.
- エピジェネティクス エピジェネティクス
背景:
- ヒストン脱メチラーゼLSD1 (ライシン特異性脱メチラーゼ1) は,表遺伝子調節における重要な酵素である.
- LSD1はヒストンH3ライシン4 (H3K4) からメチル群の除去を触媒化し,遺伝子発現に影響を与えます.
- LSD1の活動不調は,がんを含む様々な病気に関与しています.
研究 の 目的:
- LSD1.1.を標的とした新しいペプチドベースの阻害剤の設計と合成を行う.
- 開発された化合物の抑制および選択性のメカニズムを特徴付ける.
- ヒストンの改変とクロマチンの改造におけるLSD1の機能を調査するための化学的ツールを確立する.
主な方法:
- ペプチドベースの阻害剤アナログの設計と合成.
- 酵素阻害アッセイは,LSD1の活動を評価するものです.
- 作用のメカニズムを決定するために,時間依存の不活性化研究.
- 質量スペクトロメトリーにより,共振付加を特定する.
- モノアミン酸化酵素Bのような関連酵素に対する選択性プロファイリング.
主要な成果:
- 2つのペプチドベースの阻害剤アナログが合成され,化合物1はLSD1.1の強力な時間依存の不活性化を示した.
- 化合物1はプロパルギラミン基を含み,LSD1.1のFAD共因子との共性アダクトを形成する.
- 化合物1による阻害は,濃度に依存した方法でペプチド基板によって保護されました.
- 化合物1は高い選択性を示したが,モノアミン酸化酵素Bの有意な阻害は見られなかった.
- 質量スペクトロメトリーは,化合物1とFAD.の間の共性相互作用を確認しました.
結論:
- 化合物1はヒストン脱甲基酵素LSD1.1.の選択的,メカニズムベースの活性化抑制剤です.
- プロパルギラミンの機能性と共性FADアダクト形成は,その抑制作用の鍵である.
- 化合物1は,ヒストンの改変とクロマチンの改造におけるLSD1の生物学的役割の研究のための貴重な化学的探査器として機能します.
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