Du Wenyu, Cheng Zhongyu, Pan Xingming, Liu Chenhao, Yue Mingyu, Li Tianhao, Xiao Zhixi, Li Lu-Lu, Zeng Xuelan, Lin Xiaoxu, Li Fuzhuo, Dong Liao-Bin
State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
Department of Natural Medicine, School of Pharmacy Key Laboratory of Smart Drug Delivery (Ministry of Education), Fudan University, Shanghai, 201203, China.
Angew Chem Int Ed Engl. 2025 Feb 10;64(7):e202419463. doi: 10.1002/anie.202419463. Epub 2025 Jan 7.
Drimane-type merosesquiterpenoids (DMT) are a class of natural products with diverse structures and broad biological activity. Classical DMT synthesis relies on atom-inefficient plant-derived chiral pool building blocks, while alternative drimane-type building blocks such as drimenol and albicanol offer more direct routes but face production challenges. In this study, we engineered a microbial platform for efficient production of these building blocks. By optimizing the PhoN-IPK system through rational engineering and incorporating a Nudix hydrolase, we achieved a drimenol production of 398 mg/L and high albicanol titers of 1805 mg/L in shake flasks and 3.5 g/L in a bioreactor. Structural analysis and molecular dynamics simulations of the engineered PhoN provided insights into its improved catalytic efficiency. We demonstrated the utility of this platform by synthesizing several DMT using albicanol as the starting material, reducing the number of synthetic steps and improving overall efficiency as compared to classical approaches.
菖蒲烷型倍半萜类化合物（DMT）是一类具有多样结构和广泛生物活性的天然产物。传统的DMT合成依赖于原子利用率低的源自植物的手性池构建模块，而诸如去氢白菖醇和白菖醇等替代菖蒲烷型构建模块提供了更直接的路线，但面临生产挑战。在本研究中，我们构建了一个用于高效生产这些构建模块的微生物平台。通过合理工程优化PhoN-IPK系统并引入一种Nudix水解酶，我们在摇瓶中实现了398 mg/L的去氢白菖醇产量以及1805 mg/L的高白菖醇滴度，在生物反应器中达到了3.5 g/L。对工程化的PhoN进行的结构分析和分子动力学模拟揭示了其提高的催化效率。我们通过以白菖醇为起始原料合成几种DMT证明了该平台的实用性，与传统方法相比，减少了合成步骤并提高了整体效率。
