Unprecedented [5.5.5.6]Dioxafenestrane Ring Construction in Fungal Insecticidal Sesquiterpene Biosynthesis

• Published in: Angewandte Chemie Vol. 131; no. 20; pp. 6641 - 6645
• Main Authors: Zeng, Haichun, Yin, Guoping, Wei, Qian, Li, Dehai, Wang, Yi, Hu, Youcai, Hu, Changhua, Zou, Yi
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 13.05.2019
• Subjects: Biosynthese; Biosynthesis; Chemical synthesis; Chemistry; Cytochrome; Cytochrome P450; Cytochromes P450; Enzymes; Fenestrane; Flavin; Fungi; Monooxygenase; Natural products; Organic chemistry; Oxidation; Redoxenzyme; Scaffolds; Sesquiterpen-Cyclase; Sesquiterpene cyclase; Terpene
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201813722

Fenestranes, a specific class of natural products, contain four fused rings that share a central quaternary carbon atom. The fungal natural product penifulvin A (1) is a potent insecticidal sesquiterpene that features the [5.5.5.6]dioxafenestrane ring. Although the chemical synthesis of 1 has been achieved recently, the enzymes catalysing the cyclization and oxidation of FPP to 1 remain unknown. In this work, we identified a concise pathway that uses only three enzymes to produce 1. A new sesquiterpene cyclase (PeniA) generates the angular triquinane scaffold silphinene (6). A cytochrome P450 (PeniB) and a flavin‐dependent monooxygenase (PeniC) catalyse a series of oxidation reactions to transform 6 into 1, including oxidation of the C15 methyl group to a carboxylate moiety, oxidative coupling of the C15 carboxylate and the C1‐C2 olefin to form a γ‐lactone, and Baeyer–Villiger oxidation to form a δ‐lactone. Our results demonstrate the highly concise and efficient ways in which fungal biosynthetic pathways can generate complex sesquiterpene scaffolds. Drei genügen: Die Biosynthese des Fenestran‐Naturstoffs Penifulvin A verläuft über einen kurzen Reaktionsweg unter Beteiligung von nur drei Enzymen. Eine neue Sesquiterpen‐Cyclase (PeniA) erzeugt das abgewinkelte Triquinangerüst Silphinen, ein Cytochrom P450 (PeniB) katalysiert eine Serie von Oxidationsreaktionen unter Bildung des γ‐Lactons und eine Flavin‐abhängige Monooxygenase (PeniC) vermittelt eine Baeyer‐Villiger‐Oxidation zum δ‐Lacton.