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

Jian-Ming Lv, Dan Hu, Hao Gao (), Tetsuo Kushiro, Takayoshi Awakawa, Guo-Dong Chen, Chuan-Xi Wang, Ikuro Abe () and Xin-Sheng Yao ()
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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

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01813-9

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