一个 (R) - 选择性转氨酶向更高效率的西塔利普丁模拟生物合成的定向进化
Dong-Xu Jia1,2, Lei Zang1,2, Chi-De Ni1,2
1Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China.
Biotechnology and bioengineering
|April 8, 2025
概括
研究人员设计了一种强大的转氨酶 (TA) 酶,用于绿色合成西塔利普丁类似物. 这种改进的酶有效地产生高纯度的药物化合物,提供了一种新的工业制造途径.
科学领域:
- 生物催化剂和绿色化学
- 酶工程和定向进化研究
- 制药合成 制药合成
背景情况:
- 转胺酶 (TA) 催化不对称氨基化是一种绿色化学方法,用于制药类模拟合成.
- 一个关键的挑战是,对于固态阻碍子,TA的基质接受度有限.
- 西塔格利普丁是一种抗高血糖药物,用于治疗II型糖尿病.
研究的目的:
- 为了设计一个高效的 (R) - 选择性转氨酶 (TA) 用于生物合成一个sitagliptin类似物.
- 开发一种强大的酶,能够催化绝缘阻碍子的氨化.
- 为 (R) -3-amino-1-morpholino-4-(2,4,5-trifluorophenyl)butan-1-one建立一个高转化合成路径.
主要方法:
- 以往构建的 (R) - 选择性TA (ATA5) 的定向演变通过易出错的PCR,位点定向和和组合性突变发生.
- 进化变体 (ATA5/F189H/S236T/M121H) 的活性,半衰期和基质转化特征.
- 结构分析,以了解突变对酶性能的影响.
主要成果:
- 进化变体ATA5/F189H/S236T/M121H的活性增加了10.2倍,半衰期在45°C时提高了4倍.
- 这种变体在辅溶剂和无辅溶剂系统中实现了高转换 (>93%) 和异构过量 (>99%).
- 经过工程设计的TA证明了对固态阻碍基质的催化效率显著提高.
结论:
- 一个强大的 (R) 选择性转氨酶通过定向进化成功构建.
- 建立了一种新的,高效的合成路径,用于西塔利普丁类比物,实现了报告中最高的转化.
- 这些发现为使用生物催化剂工业制造西塔格利普丁类似物提供了有价值的参考.
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