サイクル化合物の選択的機能化のためのサイトクロームP450カルベントランスファーゼの誘導進化
Oliver F Brandenberg1, Kai Chen1, Frances H Arnold1
1Division of Chemistry and Chemical Engineering , California Institute of Technology , Pasadena , California 91125 , United States.
Journal of the American Chemical Society
|May 10, 2019
まとめ
研究者は,効率的なカルベンの転移反応のためのサイトクロームP450酵素を開発し,ヘテロサイクルとアルケンの選択的機能化を可能にしました. この生物触媒は 金属触媒の持続可能な代替手段として 有価な化学的構成要素を合成します
科学分野:
- 生物触媒と酵素工学
- 有機合成
- 薬剤化学
背景:
- カルベンの転移反応は,薬剤と化学的構成要素の合成に不可欠である.
- ヘモプロテイン・カルベン・トランスファーゼは,制御された機能化のための調整可能な活性部位を提供するが,ヘテロサイクルに適した酵素は稀である.
- 既存の酵素はターンオフが低いか,高価なコファクターが必要である.
研究 の 目的:
- 効率的なカルベンのヘテロサイクルとサイクルアルケンの転送のためのサイトクロームP450酵素を進化させる.
- カーベントランスファーゼの活性に指向された進化のための高通量スクリーニング方法を開発する.
- 複雑な分子合成のための生物触媒カルベンの転送の範囲を拡大する.
主な方法:
- 1-メチルインドールC3アルキル化のための高通量スペクトロフォトメトリックスクリーニングアッセイを開発した.
- P450変異を最適化するために,ランダム性および標的型変異を含む,指向進化を使用した.
- パイロルアルキル化,エナチオセレクティブ・インドルアルキル化,およびサイクロプロパネーションの活性を増強するために並行進化を行った.
主要な成果:
- 11つのアミノ酸置換と削除された還元酵素ドメインを持つP450変種が進化し,インドルC3アルキル化で470回転/分と18,000回転を達成した.
- インドールの化学選択C3アルキル化が実証された.
- 遺伝子組み換え生物触媒を用いた地域選択性ピロールアルキル化,エナチオ選択性インドルアルキル化,サイクルアルケンのサイクロプロパン化が達成された.
結論:
- エンジニアリングされたヘモプロテインは,周期的標的の選択的機能化に高度に調整できます.
- 誘導進化は 自然に新しい酵素触媒の能力を 拡張する強力なツールです
- カーベンの移転のための効率的な生物触媒を開発し,従来の金属触媒に持続可能な代替手段を提供しました.
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