Biosynthesis of JBIR-76 and -77, aromatic polyketides with isofuranonaphthoquinone scaffold

JBIR-76 and -77 are aromatic polyketides isolated from Streptomyces sp. RI-77. These compounds are derivatives of isofuranonaphthoquinone (IFNQ). IFNQ derivatives have been isolated from various organisms including microorganisms and plants. However, the biosynthetic pathways responsible for the construction of these compounds have not yet been elucidated. By draft genome sequencing, we discovered a type II polyketide synthase (PKS) gene cluster (ifn cluster) which might be responsible for the biosynthesis of JBIR-76 and -77. Gene inactivation analysis confiirmed the involvement of the ifn gene cluster in the biosynthesis of JBIR-76 and -77. The core structures of JBIR-76 and -77 are composed of 13 carbons, although the minimal PKS (IfnANO) was predicted to synthesize an octaketide intermediate composed of 16 carbons. Therefore, we assumed that a C-C bond cleavage reaction should be involved in the biosynthesis of JBIR-76 and -77. We focused on a Baeyer-Villiger monooxygenase homolog (IfnQ) encoded by the ifn gene cluster. An ifnQ disruption mutant did not produce JBIR-76 or -77 and accumulated some shunt products whose core structures were composed of 15 carbons. To further elucidate the role of IfnQ, in vitro IfnQ reaction was examined using recombinant IfnQ and putative intermediate analogs. According to the obtained results, we proposed that the Baeyer-Villiger oxidation of a bicyclic octaketide intermediate catalyzed by IfnQ is a key step for the formation of the IFNQ scaffold of JBIR-76 and -77.