在大肠杆菌中抗抑郁药psilocybin的de novo生物合成
Zhangrao Huang1,2, Yongpeng Yao1, Rouyu Di1,2
1State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People's Republic of China.
Microbial biotechnology
|April 3, 2025
概括
研究人员对大肠杆菌进行了基因工程设计,以实现可持续的西生产. 经过修改的酶和优化的途径显著增加了西的产量,为负担得起的抗抑郁药制造铺平了道路.
科学领域:
- 生物技术是生物技术.
- 代谢工程是代谢工程.
- 微生物生产 微生物生产
背景情况:
- 三胺类类化合物psilocybin在治疗耐药抑郁症方面表现有前途,需要高效的生产方法.
- 目前的psilocybin制造受到表达像PsiH这样的真核酶在 prokaryotic 系统中的挑战所限制.
- 在大肠杆菌中进行新生合成是可持续和经济地生产psilocybin的一个有希望的途径.
研究的目的:
- 通过对关键酶PsiH进行工程来克服大肠杆菌中psilocybin生物合成的局限性.
- 建立一个强大的微生物平台,用于新生产西.
- 通过路径优化和发酵改进,显著提高psilocybin的产量.
主要方法:
- 具有修饰的N端域的真核细胞细胞染色体P450酶PsiH的工程变体.
- 在低温下表达了大肠杆菌中完整的西洛生物合成途径.
- 优化了前体供应,P450电子转移链,并过度表达了甲基转移酶基因psiM.
- 为了最大限度地生产psilocybin,优化了小瓶发酵条件.
主要成果:
- 在初始途径工程后,获得了33倍的诺贝奥西斯位数 (105.3 mg/L) 和17倍的 пси洛西宾位数 (14 mg/L) 的增加.
- 通过过度表达psiM,进一步增强了psilocybin的产生,将norbaeocystin转化为psilocybin.
- 达到79.4毫克/升的最终psilocybin标位,比基线菌株改善100倍.
- 证明了真菌P450酶的成功工程,以改善大肠杆菌的催化活性.
结论:
- 工程设计的PsiH变体和优化的途径使大肠杆菌中高效的新型psilocybin合成成为可能.
- 这项研究在微生物生产西方面取得了重大进展,西是治疗抑郁症的关键化合物.
- 开发的微生物平台支持可持续和经济高效地制造用于治疗应用的psilocybin.
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