Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California 90095, United States.
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States.
ACS Synth Biol. 2022 Apr 15;11(4):1639-1649. doi: 10.1021/acssynbio.2c00037. Epub 2022 Mar 16.
Monoterpene indole alkaloids (MIAs) are an expansive class of plant natural products, many of which have been named on the World Health Organization's List of Essential Medicines. Low production from native plant hosts necessitates a more reliable source of these drugs to meet global demand. Here, we report the development of a yeast-based platform for high-titer production of the universal MIA precursor, strictosidine. Our fed-batch platform produces ∼50 mg/L strictosidine, starting from the commodity chemicals geraniol and tryptamine. The microbially produced strictosidine was purified to homogeneity and characterized by NMR. Additionally, our approach enables the production of halogenated strictosidine analogues through the feeding of modified tryptamines. The MIA platform strain enables rapid access to strictosidine for reconstitution and production of downstream MIA natural products.
单萜吲哚生物碱（MIAs）是一类广泛存在的植物天然产物，其中许多已被世界卫生组织列入基本药物清单。由于从天然植物宿主中提取的产量较低，因此需要更可靠的药物来源来满足全球需求。在这里，我们报告了一种基于酵母的平台的开发，用于高产通用 MIA 前体——strictosidine。我们的分批补料平台使用商品化的香叶醇和色胺作为起始原料，可生产约 50mg/L 的 strictosidine。通过微生物产生的 strictosidine 经过纯化达到均一性，并通过 NMR 进行了表征。此外，我们的方法还可以通过添加修饰的色胺来生产卤化 strictosidine 类似物。该 MIA 平台菌株能够快速获得 strictosidine，用于再构成和下游 MIA 天然产物的生产。
