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Chinese Journal of Organic Chemistry >

2021 , Vol. 41 >Issue 8: 3297 - 3302

DOI: https://doi.org/10.6023/cjoc202103033

NOTES

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

  • Shijie Li ,
  • Qiuyue Nie ,
  • Zhenyu Ji ,
  • Huiming Hua ,
  • Gongli Tang
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  • 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
*Corresponding author.s. E-mail: ;
E-mail:

Received date: 2021-03-20

  Revised date: 2021-04-19

  Online published: 2021-05-25

Supported by

National Key Research and Development Program of China(2018YFA0901900)

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Abstract

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

Cite this article

Shijie Li , Qiuyue Nie , Zhenyu Ji , Huiming Hua , Gongli Tang . Combinatorial Biosynthesis Mediates the Discovery of Novel Tetracyclines with Isomerized C-4 Hydroxyl[J]. Chinese Journal of Organic Chemistry, 2021 , 41(8) : 3297 -3302 . DOI: 10.6023/cjoc202103033

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