Department of Pharmacy, Guangdong Second Provincial General Hospital, Integrated Chinese and Western Medicine Postdoctoral Research Station, School of Medicine, Jinan University, Guangzhou 510317, China.
Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou 510632, China.
J Am Chem Soc. 2024 May 8;146(18):12723-12733. doi: 10.1021/jacs.4c02415. Epub 2024 Apr 23.
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 (, , , ) biosynthetic gene cluster is sufficient to yield fuscoatroside by heterologous expression in . 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.
烟曲霉素类抗生素，以烟曲霉素和 Fuscoatroside 为代表，属于真菌来源的一组独特的三萜类化合物。这些化合物具有显著的抗真菌特性，ibrexafungerp 是烟曲霉素的半合成衍生物，最近获得了 FDA 的批准，成为治疗侵袭性外阴阴道念珠菌病的第一种口服抗真菌药物。烟曲霉素类抗生素的 E 环被裂解，在裂解部位有一个氧化的羧基和一个还原的甲基，这表明它们的生物合成涉及前所未有的 C-C 键裂解化学。在这里，我们表明，一个 4 基因（，，，）生物合成基因簇通过在 中的异源表达足以产生 Fuscoatroside。值得注意的是，FsoA 是一种前所未闻的萜烯环化酶-糖基转移酶融合酶，提供了一种三萜糖苷产物，依赖于酶的融合。FsoE 是一种 P450 酶，它在 C19 处催化连续的氧化反应，促进 C-C 键的裂解，产生一个氧化的羧基和一个还原的甲基，这在已知的 P450 酶中从未观察到。因此，我们的研究为使用生物合成方法制造烟曲霉素类抗生素奠定了重要基础。
