激素S-Adenosyl-l-Methionine氧化酶DarE通过部分局部化托方Cβ激素形成以太键
Bach X Nguyen1, Melissa M Bollmeyer2, Hai Nguyen1
1Department of Biochemistry, Duke University School of Medicine, Durham, North Carolina 27710, United States.
Journal of the American Chemical Society
|January 23, 2026
概括
达罗巴克丁是针对格拉姆阴性细菌的强效抗生素,它利用由激素酶DarE形成的独特的以太交叉链. 这项研究揭示了DarE.
科学领域:
- 生物化学 生物化学
- 自然产品生物合成 自然产品生物合成
- 抗菌研究 抗菌研究
背景情况:
- 达罗巴克是核糖体合成和翻译后修饰的 (RiPPs),对抗格兰氏阴性病原体具有显著活性.
- 它们的抗生素疗效依赖于独特的β-链结构,由两个托残留物之间的以太交叉连接加强.
- 这种由激进的S-adenosyl-l-methionine (SAM) 酶DarE形成的以太结合,使用未经修改的托残留物和分子氧,在机理上与其他天然产品的以太结合不同.
研究的目的:
- 阐明DarE酶在形成达洛巴乙烯交叉链中的大部分未被探索的催化机制.
- 识别和表征关键的中间体,参与激素介导的O原子合并和以太键形成过程.
主要方法:
- 使用同位素标记的DarA及其W3变体.
- 采用动力学分析来研究酶活性.
- 应用了先进的光谱技术,包括电子磁共振 (EPR),电子核双共振 (ENDOR) 和高精度合 (HYSCORE) 光谱.
主要成果:
- 成功检测并表征了一种关键的基质中间体,W3-Cβ•,在托的Cβ位置.
- 在涉及W3变异的DarA反应中观察到类似的基因物种.
- 提供了直接的证据,即DarE通过W3-Cβ•中间体与分子氧 (O2) 反应,催化以太交叉链形成.
结论:
- 这些发现揭示了在RiPP生物合成中O原子结合的前所未有的基因介导机制.
- 这项研究提供了直接的机械洞察力,了解DarE如何在达洛巴克中形成特有的以太交叉链.
- 描述的基质中间体是理解这种新型生物合成策略的关键.
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