NzeBの構造と機能,多用途のC-CとC-N結合形成ディケトピペラジンジメラーゼ
Vikram V Shende, Yogan Khatri, Sean A Newmister
1Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States.
Journal of the American Chemical Society
|August 14, 2020
まとめ
研究者らは,複雑なダイケトピペラジンジマーを選択的に生成できる新しい酵素NzeBを特定しました. この発見により 構造とステレオ化学を 精密に制御して これらの天然物質を合成する 新しい生物触媒方法が生まれました
科学分野:
- 自然製品合成
- 酵素学
- 構造生物学
背景:
- ディメリック・ディケトピペラジン (DKPs) は,複雑な構造と貴重な生物活性を持つ天然製品です.
- 既存の合成方法では,単一のモノマーから構成的およびステレオアイソメリックDKPsの選択的形成を制御できません.
- 酵素を用いた生物触媒的アプローチは,制御されたDKP合成のための有望な道を提供します.
研究 の 目的:
- 生物触媒用途のDKPを組み立てるための生物合成酵素を特徴づける.
- NzeBの触媒的柔軟性と選択性の分子基礎を理解する.
- DKPの二分化におけるNzeBの機能の構造的および計算的根拠を提供すること.
主な方法:
- ゲノムマイニングにより,Streptomyces spのNzeB酵素を特定する. NRRL F-5053 について
- 様々な基板でNzeBの高解像度結晶構造 (1.5 Å) を決定する.
- アクティブサイト残留物の機能を検知するサイト指向型変異.
- 反応メカニズムの解明のための計算モデル.
主要な成果:
- サイトクロームP450であるNzeBは,DKP合成における分子間炭素-炭素 (C-C) と炭素-窒素 (C-N) の結合形成の両方を触媒化する.
- クリスタル構造は,NzeBの柔軟なサイト,ステレオ,および化学選択性の分子基盤を明らかにしました.
- これは,直接,分子間C-Hアミネーションを触媒するオキシダスの最初の結晶構造です.
- ミュタゲネシスと計算による研究は,残留物誘導の選択性に関する洞察を提供した.
結論:
- NzeBは,選択的なDKP二酸化を可能にする驚くべき触媒的汎用性を示しています.
- 構造と計算上のデータは,NzeBのユニークな触媒能力の根拠となります.
- この研究は,CYP450ディケトピペラジンジメラゼの理解を深め,合成化学のためのツールを提供します.
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