使用基于分子修改结网络调节的新型碳基还原酶的Vibegron中间体的高效生物合成
Xiao-Jian Zhang1, Fei Yang1, Kai-Li Chen1
1National and Local Joint Engineering Research Center for Biomanufacturing of Chiral Chemicals, Zhejiang University of Technology, Hangzhou 310014, People's Republic of China; Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310014, People's Republic of China.
Bioorganic chemistry
|August 20, 2023
概括
一种新型的工程酶,EaSDR6,显著增强了关键Vibegron中间体 (2S,3R) -氨基乙烯的合成. 这一突破实现了高产量和纯度,为改进过度活性膀治疗铺平了道路.
科学领域:
- 生物技术和生物催化剂
- 有机合成 有机合成
- 制药化学 制药化学 制药化学
背景情况:
- 维贝格龙是一种选择性的β3-上腺体受体激动剂,用于过度活跃的膀治疗.
- 甲基 (2S,3R) -2- (tert-butoxycarbonyl) -amino) -3-基-3-phenylpropanoate ((2S,3R) -aminohydroxy ester) 是Vibegron合成的一个关键的性中间体.
- 这种中间体的高效和选择性合成对于制药生产至关重要.
研究的目的:
- 为改进催化活性设计一种新型碳基还原酶 (EaSDR6).
- 开发一种高效的生物催化系统,用于 (2S,3R) -氨基乙烯的不对称合成.
- 为了优化反应条件的高产量,enantioselectivity,和时空产量.
主要方法:
- 来自GenBank的数据挖掘用于识别Exiguobacterium sp. 这种细菌. s126碳基还原酶 (EaSDR6) 的使用.
- 局部定向和突变发生和组合突变发生来增强EaSDR6活性.
- 构建一个有机-水性双相生物反应系统,用于不对称合成.
主要成果:
- 与野生类型相比,工程突变者EaSDR6A138L/S193A的活性增加了4.58倍.
- 突变酶的催化效率 (kcat/Km) 提高了5.07倍.
- 生物反应系统实现了>99.99%的产量和>99.99%的反体过量 (e.e.) 对于 (2S,3R) - 氨基基乙烯在150g/L基底度.
结论:
- 设计的EaSDR6A138L/S193A酶为合成Vibegron中间体提供了卓越的性能.
- 开发的双相生物反应系统为工业应用提供了一种高效和酶选择性方法.
- 获得的基质度和时空产量超过了之前报告的方法.
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