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Biosynthesis of helvolic acid and identification of an unusual C-4-demethylation process distinct from sterol biosynthesis

Author

Listed:
  • Jian-Ming Lv

    (Jinan University)

  • Dan Hu

    (Jinan University)

  • Hao Gao

    (Jinan University)

  • Tetsuo Kushiro

    (The University of Tokyo)

  • Takayoshi Awakawa

    (The University of Tokyo)

  • Guo-Dong Chen

    (Jinan University)

  • Chuan-Xi Wang

    (Jinan University)

  • Ikuro Abe

    (The University of Tokyo)

  • Xin-Sheng Yao

    (Jinan University)

Abstract

Fusidane-type antibiotics represented by helvolic acid, fusidic acid and cephalosporin P1 are a class of bacteriostatic agents, which have drawn renewed attention because they have no cross-resistance to commonly used antibiotics. However, their biosynthesis is poorly understood. Here, we perform a stepwise introduction of the nine genes from the proposed gene cluster for helvolic acid into Aspergillus oryzae NSAR1, which enables us to isolate helvolic acid (~20 mg L−1) and its 21 derivatives. Anti-Staphylococcus aureus assay reveals that the antibacterial activity of three intermediates is even stronger than that of helvolic acid. Notably, we observe an unusual C-4 demethylation process mediated by a promiscuous short-chain dehydrogenase/reductase (HelC) and a cytochrome P450 enzyme (HelB1), which is distinct from the common sterol biosynthesis. These studies have set the stage for using biosynthetic approaches to expand chemical diversity of fusidane-type antibiotics.

Suggested Citation

  • Jian-Ming Lv & Dan Hu & Hao Gao & Tetsuo Kushiro & Takayoshi Awakawa & Guo-Dong Chen & Chuan-Xi Wang & Ikuro Abe & Xin-Sheng Yao, 2017. "Biosynthesis of helvolic acid and identification of an unusual C-4-demethylation process distinct from sterol biosynthesis," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01813-9
    DOI: 10.1038/s41467-017-01813-9
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