在拉萨洛西德A生物合成中,由弗拉依赖的单氧化酶进行序列式选性氧化氧化的结构基础
Qian Wang1, Yaming Deng2, Dayan Viera3
1Department of Chemistry and Biochemistry, The University of Texas at El Paso, El Paso, Texas, 79968, USA.
Angewandte Chemie (International ed. in English)
|April 8, 2025
概括
黄素依赖的单氧化酶Lsd18在拉萨酸A生物合成过程中将多中间体转化为双氧化物. 结构研究揭示了Lsd18的大基板口袋和立体选择性子口袋,使设计师聚乙烯药物开发成为可能.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 自然产品生物合成 自然产品生物合成
背景情况:
- 聚乙烯聚基是具有抗微生物和抗增殖活性的天然产品.
- 拉萨洛西德A,由Streptomyces lasalocidi产生的,是这些化合物的一个关键例子.
- 酶Lsd18对于将聚中间体转化为 bis-epoxides 在拉萨酸A生物合成中至关重要.
研究的目的:
- 阐明Lsd18双重环氧化和立体选择性背后的结构机制.
- 了解Lsd18在拉萨洛酸A生产过程中如何处理聚基质.
- 为制药应用工程新型聚乙烯提供基础.
主要方法:
- 使用X射线结晶学确定了Lsd18在多个状态中的结构:无基质,基质结合和产品结合.
- 对酶基质和酶产物复合物的分析,以了解结合相互作用.
- 结构性比较以确定负责活动和选择性的关键特征.
主要成果:
- Lsd18具有异常大的基底结合口袋,可以容纳多种多聚结构.
- 这种大口袋使得基板内有两个不同的CC键的环氧化.
- 在活性部位附近的一个特定的亚囊控制着环氧化过程的立体化学结果 (R,R).
- 该酶精确地控制基质的方向,以确保立体选择性黄介导氧化.
结论:
- 对Lsd18功能的结构洞察力澄清了聚乙烯生物合成中二氧化物形成的分子基础.
- 酶的独特结构特征,包括其大口袋和立体选择性子口袋,是其催化活性的关键.
- 这种分子理解有助于合理设计Lsd18变体,以创建具有治疗潜力的新型聚化合物.
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