Journal
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
Volume 105, Issue 13, Pages 5407-5417Publisher
SPRINGER
DOI: 10.1007/s00253-021-11192-3
Keywords
Fungi; Bifunctional terpene synthases; Terpenoids; Anti-inflammatory
Categories
Funding
- National Key Research and Development Program of China [2019YFA0906200, 2020YFA090032, 2020YFA0907200]
- National Natural Science Foundation of China [21877038, 21907031, 81903529, 21977029, 31720103901, 81573341]
- Open Project Funding of the State Key Laboratory of Bioreactor Engineering
- 111 Project [B18022]
- Shanghai Rising-Star Program [20QA1402800]
- Shanghai Science and Technology Commission [18JC1411900]
- Natural Science and Engineering Research Council of Canada
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The study identified a unique BFTS sub-clade critical to the formation of a 5-15 trans-fused bicyclic sesterterpene and revealed that phytopathogenic fungi can serve as important sources of active terpenoids through systematic analysis of BFTS biosynthetic gene clusters.
Fungal terpenoids catalyzed by bifunctional terpene synthases (BFTSs) possess interesting bioactive and chemical properties. In this study, an integrated approach of genome mining, heterologous expression, and in vitro enzymatic activity assay was used, and these identified a unique BFTS sub-clade critical to the formation of a 5-15 trans-fused bicyclic sesterterpene preterpestacin I (1). The 5-15 bicyclic BFTS gene clusters were highly conserved but showed relatively wide phylogenetic distribution across several species of the diverged fungal classes Dothideomycetes and Sordariomycetes. Further genomic organization analysis of these homologous biosynthetic gene clusters from this clade revealed a glycosyltransferase from the graminaceous pathogen Bipolaris sorokiniana isolate BS11134, which was absent in other 5-15 bicyclic BFTS gene clusters. Targeted isolation guided by BFTS gene deletion led to the identification of two new sesterterpenoids (4, and 6) from BS11134. Compounds 2 and 4 showed moderate effects on LPS-induced nitrous oxide production in the murine macrophage-like cell line RAW264.7 with in vitro inhibition rates of 36.6 +/- 2.4% and 24.9 +/- 2.1% at 10 mu M, respectively. The plausible biosynthetic pathway of these identified compounds was proposed as well. This work revealed that phytopathogenic fungi can serve as important sources of active terpenoids via systematic analysis of the genomic organization of BFTS biosynthetic gene clusters, their phylogenetic distribution in fungi, and cyclization properties of their metabolic products.
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