Synthetic Biology for Clinical and Technological Innovation, National University of Singapore, 28 Medical Drive, Singapore, 117456, Singapore.
Synthetic Biology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore.
Nat Commun. 2022 Feb 7;13(1):712. doi: 10.1038/s41467-022-28386-6.
The ergot alkaloids are a class of natural products known for their pharmacologically privileged molecular structure that are used in the treatment of neurological ailments, such as Parkinsonism and dementia. Their synthesis via chemical and biological routes are therefore of industrial relevance, but suffer from several challenges. Current chemical synthesis methods involve long, multi-step reactions with harsh conditions and are not enantioselective; biological methods utilizing ergot fungi, produce an assortment of products that complicate product recovery, and are susceptible to strain degradation. Reconstituting the ergot alkaloid pathway in a strain strongly amenable for liquid fermentation, could potentially resolve these issues. In this work, we report the production of the main ergoline therapeutic precursor, D-lysergic acid, to a titre of 1.7 mg L in a 1 L bioreactor. Our work demonstrates the proof-of-concept for the biological production of ergoline-derived compounds from sugar in an engineered yeast chassis.
麦角生物碱是一类具有药理学优势的天然产物，其分子结构独特，用于治疗帕金森病和痴呆等神经疾病。因此，通过化学和生物途径合成这些生物碱具有工业相关性，但存在一些挑战。目前的化学合成方法涉及长而多步的反应，条件苛刻，且不具有对映选择性；而利用麦角真菌的生物方法会产生一系列产物，这使得产物的回收变得复杂，并且容易受到菌株降解的影响。在一个适合液体发酵的菌株中重新构建麦角生物碱途径，可能会解决这些问题。在这项工作中，我们报告了在 1L 生物反应器中以 1.7mg/L 的浓度生产主要的麦角林治疗前体 D-麦角酸。我们的工作证明了在工程酵母底盘中从糖生物合成麦角衍生化合物的概念验证。
