Biosynthesis of Enfumafungin-type Antibiotic Reveals an Unusual Enzymatic Fusion Pattern and Unprecedented C–C Bond Cleavage

作者：Zhiqin Cao, Gao‐Qian Wang, Ray Luo, Yaohui Gao, Jian‐Ming Lv, Shengying Qin, Guo‐Dong Chen, Takayoshi Awakawa, Xue-Feng Bao, Qinghua Mei, Xin‐Sheng Yao, Dan Hu, Ikuro Abe, Hao Gao · 发表于：Journal of the American Chemical Society · 年份：2024 · DOI：10.1021/jacs.4c02415 · 被引用次数：20 · 研究领域：Microbial Natural Products and Biosynthesis、Phytochemical compounds biological activities、Natural product bioactivities and synthesis

Enfumafungin-type antibiotics, represented by enfumafungin and fuscoatroside, belong to a distinct group of triterpenoids derived from fungi. These compounds exhibit significant antifungal properties with ibrexafungerp, a semisynthetic derivative of enfumafungin, recently gaining FDA’s approval as the first oral antifungal drug for treating invasive vulvar candidiasis. Enfumafungin-type antibiotics possess a cleaved E-ring with an oxidized carboxyl group and a reduced methyl group at the break site, suggesting unprecedented C–C bond cleavage chemistry involved in their biosynthesis. Here, we show that a 4-gene ( fsoA, fsoD, fsoE, fsoF ) biosynthetic gene cluster is sufficient to yield fuscoatroside by heterologous expression in Aspergillus oryzae . Notably, FsoA is an unheard-of terpene cyclase-glycosyltransferase fusion enzyme, affording a triterpene glycoside product that relies on enzymatic fusion. FsoE is a P450 enzyme that catalyzes successive oxidation reactions at C19 to facilitate a C–C bond cleavage, producing an oxidized carboxyl group and a reduced methyl group that have never been observed in known P450 enzymes. Our study thus sets the important foundation for the manufacture of enfumafungin-type antibiotics using biosynthetic approaches.