Involvement of the Baeyer–Villiger Monooxygenase IfnQ in the Biosynthesis of Isofuranonaphthoquinone Scaffold of JBIR‐76 and ‐77

Abstract

JBIR-76 and -77 are isofuranonaphthoquinones (IFNQs) isolated from Streptomyces sp. RI-77. Draft genome sequencing and gene disruption analysis of Streptomyces sp. RI-77 showed that a type II polyketide synthase (PKS) gene cluster (ifn cluster) was responsible for the biosynthesis of JBIR-76 and -77. It was envisaged that an octaketide intermediate (C16 ) could be synthesized by the minimal PKS (IfnANO) and that formation of the IFNQ scaffold (C13 ) would therefore require a C-C bond cleavage reaction. An ifnQ disruptant accumulated some shunt products (C15 ), which were presumably produced by spontaneous cyclization of the decarboxylated octaketide intermediate. Recombinant IfnQ catalyzed the Baeyer-Villiger oxidation of 1-(2-naphthyl)acetone, an analogue of the bicyclic octaketide intermediate. Based on these results, we propose a pathway for the biosynthesis of JBIR-76 and -77, involving IfnQ-catalyzed C-C bond cleavage as a key step in the formation of the IFNQ scaffold.

New isofuranonaphthoquinones and isoindolequinones from Streptomyces sp. CB01883

“…RI-77. 6 We also showed that simply mixing IFQ A (1) with anthranilamide in refluxing ethanol afforded IIQ B (9) and the reaction could be accelerated upon acid catalysis, supporting the proposal that IIQs may be derived nonenzymatically from IFQs in the presence of an amine.…”

“…3 The IFQs have been reported to have antibacterial, antioxidant, antiplasmodial, cytotoxic and Fe(III) chelation activities. [3][4][5][6] Nothing was known about IFQ biosynthesis until the recent cloning and characterization of the ifn gene cluster from Streptomyces sp. RI-77, which was confirmed experimentally to encode the production of two IFQs JBIR-76 and JBIR-77 (Figure 2a).…”

“…RI-77, which was confirmed experimentally to encode the production of two IFQs JBIR-76 and JBIR-77 (Figure 2a). 5,6 JBIR-76 and JBIR-77 biosynthesis featured a type II polyketide synthase that assembles an octaketide intermediate from malonyl CoA precursors and a Baeyer-Villiger monooxygenase that catalyzes a key C-C bond cleavage, affording the characteristic IFQ scaffold of JBIR-76 and JBIR-77 (Figure 2b). 6 The biosynthetic origin of IIQs and their relationship to IFQs have not been addressed.…”

“…5,6 JBIR-76 and JBIR-77 biosynthesis featured a type II polyketide synthase that assembles an octaketide intermediate from malonyl CoA precursors and a Baeyer-Villiger monooxygenase that catalyzes a key C-C bond cleavage, affording the characteristic IFQ scaffold of JBIR-76 and JBIR-77 (Figure 2b). 6 The biosynthetic origin of IIQs and their relationship to IFQs have not been addressed. It is worth noting that IIQs are always co-isolated with related IFQs and have been prepared upon heating the related IFQs with an amine (albeit in low yields).…”

“…4,24 Identification of the ifq Cluster and a proposed biosynthetic pathway for IFQs Inspired by the recently reported ifn gene cluster from Streptomyces sp. RI-77, which was confirmed to encode the biosynthesis of JBIR-76 and JBIR-77, 6 two IFQs structurally similar to 1-6 (Figure 2), we decided to identify the ifq gene cluster in Streptomyces sp. CB01883 to shed light on IFQ and IIQ biosynthesis.…”