由结构引导的进化,以改善来自Bacillus subtilis的aldo-keto减少酶 yhdN的催化性能,以制备奇拉性二甲基α-基胺胺
1Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China.
International journal of biological macromolecules
|April 21, 2025
概括
一种阿尔多-基因还原酶 (yhdN) 的结构导向进化使得可有效地生物催化地产生奇拉性二甲基α-基胺基. 工程变种实现了高转换和药物合成的酶选择性.
科学领域:
- 生物催化和酶工程 生物催化和酶工程
- 有机合成 有机合成
- 制药化学 制药化学 的相关文章
背景情况:
- 基拉尔二甲基α-基胺是制药的关键组成部分.
- 由于大量的基替代剂,这些化合物的酶选择性合成具有挑战性.
- 使用还原酶的生物催化剂提供了一个潜在的途径,但在活性和立体选择性方面面临限制.
研究的目的:
- 为了设计一种阿尔多-基因还原酶 (yhdN),以改善diarylα-hydroxy amides的酶选择性还原.
- 开发一种生物催化方法,有效合成有价值的性药物中间体.
主要方法:
- 细菌亚菌的结构导向进化是aldo-keto减少酶 (yhdN).
- 构建立体补充酶变体 (W126F/W21S/A56T和W126A/W21A/P325V) 的方法.
- 工程变体在用GDH进行全细胞生物催化剂中的应用.
- 分子对接和分子动力学 (MD) 模拟以阐明机制.
主要成果:
- 经过工程改造的 yhdN 变种实现了高转换率 (>98%) 和出色的反抗选择性 (>97% e.e.) 对于N-phenyl-2-hydroxy-2-phenylacetamide,在3小时内使用.
- 立体补充变体能够获得 (S) 和 (R) 双反体.
- 在W21和W126的突变被确定为重塑基质结合口袋和通过π-π/π-基相互作用增强立体选择性的关键.
- 变体GDH全细胞催化剂显示了增强的适用性.
结论:
- 结构导向进化成功地为奇拉性二甲基α-基胺制造了高效和立体选择性的生物催化剂.
- 这项研究提供了一种新的酶催化转化,用于访问具有挑战性的性药物动机.
- 工程变体和机械洞察力为可持续合成性化合物提供了一个有希望的平台.
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