Guo Zizheng, Zhou Ying, Li Jiangqi, Liu De, Huang Yuwen, Zhang Yu, Yu Rongmin, Zhu Jianhua
Biotechnological Institute of Chinese Materia Medica, Jinan University, Guangzhou, 511443, China.
Department of Natural Product Chemistry, Jinan University, Guangzhou, 511443, China.
Nat Commun. 2025 Apr 24;16(1):3888. doi: 10.1038/s41467-025-59312-1.
Dihydroartemisinic acid (DHAA) converts into antimalarial drug artemisinin (ART) by auto-oxidation. High production of artemisinic acid (AA) has been achieved by fermentation of engineered Saccharomyces cerevisiae, and AA can be converted into ART through DHAA by chemical synthesis. However, there is no enzyme reported to catalyze the conversion of AA to DHAA. Here, we report a dihydroartemisinic acid dehydrogenase (AaDHAADH) from Artemisia annua L, which catalyzes the bidirectional conversion between AA and DHAA. An optimized mutant AaDHAADH (P26L) is obtained through site-directed mutagenesis and its activity toward AA is 2.82 times that of the original gene. De novo synthesis of DHAA is achieved in S. cerevisiae using the targeted optimized gene AaDHAADH (P26L). Furthermore, 3.97 g/L of DHAA is obtained by fermentation of engineered S. cerevisiae in 5 L bioreactor. The discovery of AaDHAADH provides a more convenient and efficient alternative route for ART biosynthesis.
二氢青蒿酸（DHAA）通过自氧化转化为抗疟药物青蒿素（ART）。通过工程酿酒酵母发酵已实现青蒿酸（AA）的高产，并且AA可通过化学合成经DHAA转化为ART。然而，尚无报道称有酶催化AA向DHAA的转化。在此，我们报道了来自黄花蒿的一种二氢青蒿酸脱氢酶（AaDHAADH），它催化AA和DHAA之间的双向转化。通过定点诱变获得了优化的突变体AaDHAADH（P26L），其对AA的活性是原始基因的2.82倍。使用靶向优化基因AaDHAADH（P26L）在酿酒酵母中实现了DHAA的从头合成。此外，通过在5 L生物反应器中对工程酿酒酵母进行发酵获得了3.97 g/L的DHAA。AaDHAADH的发现为青蒿素生物合成提供了一种更便捷高效的替代途径。
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