Sakuranetin, a flavonoid phytoalexin, has demonstrated neuroprotective properties and exhibits tyrosinase inhibitory activities, making it highly valuable in the cosmetics and pharmaceutical industries. In this study, we engineered a Yarrowia lipolytica strain for the high-titer de novo production of sakuranetin using glucose as a substrate. To effectively enhance sakuranetin production, we implemented a multimodule engineering strategy that included optimizing the sakuranetin synthesis pathway, designing a regeneration system for the methyl donor S-adenosyl methionine, increasing the malonyl-CoA precursor supplement, and constructing the feedback inhibition-relieved shikimate pathway. Moreover, a transcriptomic analysis was conducted to identify potential targets for further improving sakuranetin synthesis. As a result, the titer of de novo synthesized sakuranetin reached 344.0 mg/L from glucose in a 5 L bioreactor. These achievements hold significant promise for the sustainable and large-scale production of sakuranetin through industrial biomanufacturing.

中文翻译：

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用于 Yarrowia lipolytica 中 Sakuranetin 高滴度从头生产的细胞内代谢的多模块合成重新设计


樱花素是一种类黄酮植物抗毒素，已显示出神经保护特性并具有酪氨酸酶抑制活性，使其在化妆品和制药行业中具有很高的价值。在这项研究中，我们设计了一种 Yarrowia lipolytica 菌株，用于以葡萄糖为底物高滴度从头生产樱花素。为了有效提高樱霉素的产生，我们实施了多模块工程策略，包括优化樱霉素合成途径、为甲基供体 S-腺苷甲硫氨酸设计再生系统、增加丙二酰辅酶 A 前体补充剂以及构建反馈抑制缓解的莽草酸盐途径。此外，进行了转录组学分析以确定进一步改进樱花素合成的潜在靶点。结果，在 5 L 生物反应器中，从葡萄糖中从头合成的樱花素的滴度达到 344.0 mg/L。这些成就为通过工业生物制造可持续和大规模生产樱花素带来了重大希望。