シャルトルーシン生物合成における最終酸化再配列の分子基礎
Yi Shuang Wang1, Bo Zhang1, Jiapeng Zhu2
1State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, School of Life Sciences , Nanjing University , Nanjing 210023 , China.
Journal of the American Chemical Society
|August 2, 2018
まとめ
研究者達は新しい酵素 ChaP を発見し 抗腫瘍化合物 チャートルーシン の複雑な構造を形成する上で 決定的な役割を果たしました このダイオキシゲネーゼはフラビン活性化酸素を利用し,天然産物の生合成における酸化再構成に関する新しい洞察を明らかにしています.
科学分野:
- 生化学と天然製品の生合成
- 酵素学とタンパク質構造
- 化学生物学
背景:
- 酸化再配列は,2型ポリケチド合成酵素 (PKS) によって合成された天然製品の構造的多様性および生物活性を生成するために不可欠である.
- 強力な抗腫瘍剤であるカルトルーシン (1) は,タイプII PKS経路から発生するユニークなペンタサイクリック芳香性ビラクトンアグリコンを特徴としています.
研究 の 目的:
- チャートルーシン生物合成における最終的なα-ピロン環形成に責任を負う酵素を特定し,特徴づけること.
- この新しい酵素によって触媒化された酸化再構成の分子機構を解明する.
主な方法:
- ダイオキシゲナーゼ ChaPとその同類体の生化学的特徴
- ChaPと関連する酵素の3次元構造を決定するX線結晶学.
- 酵素と基板の相互作用と触媒メカニズムを調査するための計算によるドッキング研究とサイト指向型変異.
主要な成果:
- 前例のないダイオキシゲネーゼであるChaPは,フラビン活性化酸素を用いたチャートルシン生物合成における末端α-ピロン環形成の触媒として特定された.
- 構造とメカニズムの研究により,乳酸化が続く2つの連続的なC-C結合分裂を含む新しい酸化再配置が明らかになった.
- ChaPは,固有のフラビン結合部位のない,フラビン活性化酸素を使用する,近隣の酸素ケラート (VOC) 酵素スーパーファミリー内の新しいクラスを表します.
結論:
- ChaPはチャートルーシンの複雑な構造とおそらくその生物学的活動に不可欠なユニークな酸化再配置を触媒にします.
- ChaPの発見は,既知のダイオキシゲネーゼのレパートリーを拡張し,フラビンに依存した酸素活性化における新しいメカニズムを強調しています.
- この研究は,複雑な自然産物の生物合成を理解するための分子基盤を提供し,酵素工学の道を開きます.
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