Identification and Characterization of the StreptazoneE Biosynthetic Gene Cluster in Streptomyces sp MSC090213JE08

Streptazone derivatives isolated from Streptomyces species are piperidine alkaloids with a cyclopenta[b]pyridine scaffold. Previous studies indicated that these compounds are polyketides, but the biosynthetic enzymes responsible for their synthesis are unknown. Here, we have identified the streptazoneE biosynthetic gene cluster in Streptomycessp. MSC090213JE08, which encodes a modular typeI PKS and tailoring enzymes that include an aminotransferase, three oxidoreductases, and two putative cyclases. The functions of the six tailoring enzymes were analyzed by gene disruption, and two putative biosynthetic intermediates that accumulated in particular mutants were structurally elucidated. On the basis of these results, we propose a pathway for the biosynthesis of streptazoneE in which the two putative cyclases of the nuclear transport factor2-like superfamily are responsible for C-C bond formation coupled with epoxide ring opening to give the five-membered ring of streptazoneE.