Aspergillus oryzae Biosynthetic Platform for de Novo Iridoid Production
Aspergillus oryzae Biosynthetic Platform for de Novo Iridoid Production
复制标题
用于从头生产环烯醚萜类化合物的米曲霉生物合成平台
DOI：
10.1021/acs.jafc.0c06563
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发表时间：
2021-02-18
影响因子：
6.1
通讯作者：
Li, Mu
中科院分区：
文献类型：
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作者：
Duan, Yali;Liu, Jiawei;Li, Mu
环烯醚萜类化合物及其衍生物单萜吲哚生物碱（MIA）是两大类具有重要药用价值的植物源天然产物。然而，较差的来源限制了它们的应用。荆芥内酯醇是MIA的一种常见环烯醚萜骨架，在酿酒酵母中异源产生。虽然在S.虽然通过代谢工程获得了酿酒酵母，但固有的代谢约束对生产施加了限制。在此，我们开发了一个高产荆芥内酯的Aspergillusplateau菌株。首先，在异戊烯焦磷酸（IPP）高产菌株A.成功合成了荆芥内酯醇。第二，同时实现了IPP供应的改善和副产物香茅醇形成的抑制。最后，通过对碳源的优化，工程菌合成荆芥拉酚的最高效价达到7.2mg/L。据我们所知，这是微生物细胞中报道的荆芥拉酚的最高滴度。所开发的A-100菌株代表了用于从头生产环烯醚萜和MIA的有吸引力的生物合成平台宿主。
The iridoids and their derivatives monoterpene indole alkaloids (MIAs) are two broad classes of plant-derived natural products with valuable pharmaceutical properties. However, the poor source limited their application. Nepetalactol, a common iridoid scaffold of MIAs, was heterologously produced in Saccharomyces cerevisiae. Although the optimization of nepetalactol production in S. cerevisiae was achieved by metabolic engineering, the inherent metabolic constraints impose a restriction on the production. Herein, we developed a high nepetalactol-producing Aspergillus oryzae platform strain. First, the co-expression of 5 nepetalactol biosynthetic genes, in a high isopentenyl pyrophosphate (IPP)-producing strain A. oryzae AK2, succeeded in the biosynthesis of nepetalactol. Second, the improvement of the IPP supply and the suppression of the byproduct citronellol formation were simultaneously achieved. Finally, the highest titer of nepetalactol of 7.2 mg/L was obtained with the engineered strain, after the optimization of the carbon source. To the best of our knowledge, this is the highest reported titer of nepetalactol in microbial cells. The developed A oryzae strain represents an attractive biosynthetic platform host for the de novo production of iridoids and MIAs.