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

Abstract

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.

Biosynthesis of the fungal glyceraldehyde-3-phosphate dehydrogenase inhibitor heptelidic acid and mechanism of self-resistance

“…These modications are proposed to be catalysed by cytochrome P450s enzymes encoded in the hep BGC, requiring molecular oxygen as the oxidant. 32,33 The emergence of 3-5 under stationary culture may hence be a result of lower aeration of the stationary culture compared to under shaking conditions.…”

Direct Synthesis of Substituted (Z)‐Allylic Sulfones by Palladium‐Catalyzed Sulfonylation of Vinylethylene Carbonates with Sodium Sulfinates

“…(3)]. [18] To gain insight into the source of the hydroxyl proton in the desired products, deuterated water (D 2 O) was added to the reaction as an additive (Scheme 6, also see SI). Surprisingly, the hydroxyl proton was not replaced with D from deuterated water.…”

The Oxidation Cascade of a Rare Multifunctional P450 Enzyme Involved in Asperterpenoid A Biosynthesis

“…f) ( Zhou et al, 2021 ). More and more research studies have found that some P450s can be involved in the oxidation reactions with multiple sites of molecules ( Bai et al, 2020 ; Child et al, 2019 ; Erickson et al, 2007 ; Yanni et al, 2008 ; Zeng et al, 2019 ) and catalyze non-oxidation reactions ( Bai et al, 2020 ; Keyler et al, 2003 ; Long and Dolan, 2001 ; Peyronneau et al, 2012 ), which are classified as multifunctional P450s. In reported multifunctional P450 family, only few oxidation cascades have been demonstrated ( Cochrane and Vederas, 2014 ; Erickson et al, 2007 ; Mendez et al, 2014 ; Moses et al, 2015 ; Narita et al, 2016 ; Zeng et al, 2019 ).…”