Sammendrag
The biosynthesis of the previously described macrolactam antibiotic BE-14106 [1] has been studied in a Streptomyces strain newly isolated from marine sediments collected in the Trondheim fjord (Norway). BE-14106 exhibits antibacterial, antifungal and anticancer activity. The BE-14106 biosynthetic gene cluster has been isolated and sequenced through screening of a genomic cosmid library and the role of the individual enzymes encoded in the cluster has been studied through bioinformatic analyses, gene inactivations, feeding experiments and enzyme assays with heterologously expressed proteins. The proposed biosynthetic pathway involves two distinct PKS systems, one for the synthesis of an acyl chain and the second for the synthesis of the macrolactam ring. The acyl chain is further processed into an aminoacyl starter for the macrolactam ring synthesis through the action of enzymes similar to NRPS domains as well as other amino acid processing enzymes. Starter units for macrolactam biosynthesis is usually derived from amino acids and this way of converting an acyl chain into an aminoacyl is thought to represent a new mechanism for generating an aminoacyl starter unit for macrolactam biosynthesis.