Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (8): 3297-3302.DOI: 10.6023/cjoc202103033 Previous Articles     Next Articles



李世杰a, 聂秋玥b, 季珍瑜b, 华会明a,*(), 唐功利a,b,*()   

  1. a 沈阳药科大学中药学院 基于靶点的药物设计与研究教育部重点实验室 沈阳 110016
    b 中国科学院上海有机化学研究所 上海 200032
  • 收稿日期:2021-03-20 修回日期:2021-04-19 发布日期:2021-05-25
  • 通讯作者: 华会明, 唐功利
  • 基金资助:

Combinatorial Biosynthesis Mediates the Discovery of Novel Tetracyclines with Isomerized C-4 Hydroxyl

Shijie Lia, Qiuyue Nieb, Zhenyu Jib, Huiming Huaa(), Gongli Tanga,b()   

  1. a Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016
    b Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032
  • Received:2021-03-20 Revised:2021-04-19 Published:2021-05-25
  • Contact: Huiming Hua, Gongli Tang
  • Supported by:
    National Key Research and Development Program of China(2018YFA0901900)

During the biosynthesis of SF2575, a tetracycline antibiotic, the ketone of C-4 in 4-keto-anhydrotetracycline (4-keto-ATC, 2) is reduced by SsfF to form (R)-4-hydroxyl-ATC (7) which can be further transformed to the final product. According to the previous study, gene cluster tjh mediates the production of a series of new tetracyclines. Three new compounds in ΔtjhO5::2R mutant which are structurally similar with 4-keto-ATC but with (S)-C-4 were obtained. TjhD2 with high similarity with SsfF revealed by bioinformatic analysis indicates that these two enzymes may exhibit the similar enzymatic function. Two new tetracyclines via complementation of ssfF encoding C-4 ketone reductase into ΔtjhD2 mutant were successfully obtained. C-4 of these two compounds is all isomerized and 15 is the aglycone of 16. The combinatorial biosynthesis strategy not only successfully discovers two new natural products, but also verifies the function of TjhD2. Moreover, although TjhD2 and SsfF possess the similar catalytic function, they mediate the production of compounds with different configuration. These results may be applied in modification of tetracyclines and lay the foundation for further exploring the specific mechanism of stereoselective reduction of ketoreductases.

Key words: combinatorial biosynthesis, biosynthesis, type II polyketides, tetracycline, isomerization