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SET7/9-触媒ライシンメチル化の基質区分された移行状態
Shi Chen, Kanishk Kapilashrami, Chamara Senevirathne
1Department of Biochemistry , Albert Einstein College of Medicine , Bronx , New York 10461 , United States.
Journal of the American Chemical Society
|April 30, 2019
まとめ
酵素は複数の移行状態 (TS) を安定させ,効率的な触媒化を行うことができる. SET7/9酵素は,異なる基質をメチル化するために2つの異なるTSを使用しており,これは酵素の汎用性を理解するために重要な発見である.
科学分野:
- 生物化学
- 酵素学
- 構造生物学
背景:
- 酵素反応は,速度の加速のために移行状態 (TS) 安定化に依存する.
- 酵素が単一の反応で複数のTSを安定させることができるかどうかを理解することは,依然として重要な課題である.
- タンパク質リジンメチルトランスフェラーゼ (PKMTs) は,表遺伝子調節に関与する重要な酵素である.
研究 の 目的:
- PKMT SET7/9が複数の異なる移行状態に対応して利用できるかどうかを調査する.
- SET7/9の基板依存型TS安定化の構造的および機械的基礎を解明する.
- 酵素効率と基板の乱交性に対する複数のTSの影響を調査する.
主な方法:
- 反応メカニズムを調査するために,実験的な運動同位体効果を使用した.
- トランジション状態の構造を決定し,制限する計算方法を使用した.
- その生理学的基質であるH3とp53との複合体におけるSET7/9酵素に焦点を当てた.
主要な成果:
- SET7/9は,H3K4とp53K372をメチル化するために,2つの構造的に異なる移行状態を採用することを実証した.
- これらのTSは,それぞれほぼ対称なSN2と非常に初期のSN2として特徴付けられました.
- これらのSET7/9 TSは,他のPKMTについて報告されたものとは異なる.
結論:
- SET7/9は,メチル化を触媒化する複数の移行状態を利用することで,顕著な柔軟性を発揮します.
- この複数のTS戦略は,SET7/9の広範囲の基板特異性および高い触媒効率のために不可欠である.
- 複数のTS安定化が他のPKMTおよび酵素における一般的なメカニズムである可能性を示唆している.
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