ノナクチンマクロサイクルにおけるステレオ化学の交替パターンは,抗菌活性と効率的なイオン結合のために必要である
Brian R Kusche1, Adrienne E Smith, Michele A McGuirl
1Department of Chemistry and Biochemistry, University of Montana, 32 Campus Drive, Missoula, Montana 59812-1656, USA.
Journal of the American Chemical Society
|November 12, 2009
まとめ
抗生物質のイオノフォールであるノナクチンの自然なステレオ化学は,抗菌活動とカリウムイオン輸送能力に不可欠です. ノナクチンの機能には,ノナクチン酸の両方のエナントオマーが必要である.
科学分野:
- バイオケミストリー バイオケミストリー
- 微生物学 微生物学とは
- 化学生物学 化学生物学とは
背景:
- ノナクチン (Nonactin) はポリケチド抗生物質であり,Streptomyces griseus.によって産生されるカリウム選択性イオノフォールである.
- それはS4対称性を持ち,アキラルであり,2つの (+) - ノナクチ酸と2つの (-) - ノナクチ酸のモノメアのサイクルテトラエステルです.
- ノナクチンの自然なステレオ化学は,その生物学的活動に不可欠ですが,そのエナティオメール組成の正確な役割は完全に解明されていません.
研究 の 目的:
- ノナクチンのイオノフォリックおよび抗菌特性のために (+) -および (-) - ノナクチン酸エナントオメアの必要性を調査する.
- 自然のノナクチンの結合親和性と輸送能力を,ノナクチンの単一のエナントイオマーから構成されたそのダイアステレオアイソマーと比較する.
主な方法:
- 2つの非天然のダイアステレオアイソマーの合成:オール・(+) ノナクチンとオール・(-) ノナクチン.
- グラム陽性生物に対する抗菌作用の決定.
- 結合熱力学 (K(a),DeltaG,DeltaH,DeltaS) を K(+),Na(+),NH(4)(+) と定量化するための同熱タイトリング熱測定法.
- 有機溶媒のイオン輸送を評価するためのピクレート分割測定法.
- イオン-リガンド複合体内のステリック相互作用を分析するための計算モデリング.
主要な成果:
- 非天然のダイアステレオアイソマーは,天然のノンアクチンと比較して,グラム陽性細菌に対して500倍も有効ではなかった.
- 天然のノナクチンは,オール・オール・ノナクチンの880倍以上の結合親和性をK ((+)) に示した.
- ノナクチンとは異なり,オール・(-) ノナクチンはK (((+)) イオンを有機溶媒に分割できませんでした.
- モデリングは,オール- ((-) -ノナクチン-K ((+)) 複合体のステリック障害を示し,緊密な結合を防止しました.
結論:
- 生物学的活性なノナクトインの形成には, (+) - ノナクトイン酸と (-) ノナクトイン酸の両方のエナンチオメアの存在が不可欠である.
- ノナクチンの固有のステレオケミストリーは,イオノフォアカリウムとしての有効性と,抗菌性の性質を決定する.
- ステレオ化学的要件を理解することで,イオン輸送と抗生物質の作用の仕組みの洞察が得られます.
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