Biosynthetic pathway for furanosteroid demethoxyviridin and identification of an unusual pregnane side-chain cleavage

Gao-Qian Wang, Guo-Dong Chen, Sheng-Ying Qin, Dan Hu (), Takayoshi Awakawa, Shao-Yang Li, Jian-Ming Lv, Chuan-Xi Wang, Xin-Sheng Yao, Ikuro Abe () and Hao Gao ()
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Gao-Qian Wang: Jinan University
Guo-Dong Chen: Jinan University
Sheng-Ying Qin: First Affiliated Hospital of Jinan University
Dan Hu: Jinan University
Takayoshi Awakawa: The University of Tokyo
Shao-Yang Li: Jinan University
Jian-Ming Lv: Jinan University
Chuan-Xi Wang: Jinan University
Xin-Sheng Yao: Jinan University
Ikuro Abe: The University of Tokyo
Hao Gao: Jinan University

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Furanosteroids, represented by wortmannin, viridin, and demethoxyviridin, are a special group of fungal-derived, highly oxygenated steroids featured by an extra furan ring. They are well-known nanomolar-potency inhibitors of phosphatidylinositol 3-kinase and widely used in biological studies. Despite their importance, the biosyntheses of these molecules are poorly understood. Here, we report the identification of the biosynthetic gene cluster for demethoxyviridin, consisting of 19 genes, and among them 15 biosynthetic genes, including six cytochrome P450 monooxygenase genes, are deleted. As a result, 14 biosynthetic intermediates are isolated, and the biosynthetic pathway for demethoxyviridin is elucidated. Notably, the pregnane side-chain cleavage requires three enzymes: flavin-dependent Baeyer-Villiger monooxygenase, esterase, and dehydrogenase, in sharp contrast to the single cytochrome P450-mediated process in mammalian cells. Structure–activity analyses of these obtained biosynthetic intermediates reveal that the 3-keto group, the C1β–OH, and the aromatic ring C are important for the inhibition of phosphatidylinositol 3-kinase.

Date: 2018
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DOI: 10.1038/s41467-018-04298-2

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