By utilizing the conformational selectivity of biosynthesis and the flexibility of chemical synthesis, researchers have formulated metabolic engineering-based semi-synthetic approaches that initiate with the final product’s structure and identify key biosynthesis intermediates. Nonetheless, these tailored semi-synthetic routes focused on end-products, neglecting the possibility of biobased intermediates as a platform for derivatization. To address this challenge, this studyproposed a novel strategy resembling chemosynthesis-style divergent exploration to amplify the significance of biobased intermediates, in the case of geranylgeraniol (GGOH). Using the novel bifunctional terpene synthase PTTC066 and systematic metabolic engineering modifications, the engineered yeast straindemonstrated high GGOH production levels (3.32 g/L, 0.039 g/L/h). This platformenabled the semi-synthesis of various pharmaceuticals, including the anti-ulcer drug teprenone, the osteoporosis treatment drug menaquinone-4, and introduced a novel route for synthesizingα-tocotrienol. This study offers a fresh outlook on semi-synthetic approaches, opening avenues for improvements, substitutions, and innovations in industrial production processes.

中文翻译：

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香叶基香叶醇：用于合成替普瑞酮、menaquinone-4 和 α-生育三烯酚的生物平台


通过利用生物合成的构象选择性和化学合成的灵活性，研究人员制定了基于代谢工程的半合成方法，该方法从最终产品的结构开始并确定关键的生物合成中间体。尽管如此，这些定制的半合成路线侧重于最终产品，忽略了生物基中间体作为衍生化平台的可能性。为了应对这一挑战，本研究提出了一种类似于化学合成式发散探索的新策略，以放大生物基中间体的重要性，以香叶基香叶醇（GGOH）为例。使用新型双功能萜烯合酶 PTTC066 和系统代谢工程修饰，工程酵母菌株表现出高 GGOH 生产水平（3.32 g/L，0.039 g/L/h）。该平台实现了多种药物的半合成，包括抗溃疡药物替普瑞酮、骨质疏松治疗药物menaquinone-4，并引入了合成α-生育三烯酚的新路线。这项研究为半合成方法提供了全新的前景，为工业生产过程的改进、替代和创新开辟了途径。