Discovery of a novel analogue of FR901533 and the corresponding biosynthetic gene cluster fromStreptosporangium roseumNo. 79089

FR901533 (1, also known as WS79089B), WS79089A (2), and WS79089C (3) are polycyclic aromatic natural products with promising inhibitory activity to endothelin-converting enzymes. In this work, we isolated five tridecaketide products fromStreptosporangium roseumNo. 79089, including1-3, benaphthamycin (4) and a novel FR901533 analogue (5). The structure of5was characterized based on spectroscopic data. Compared with the major product2, the new compound5has an additional hydroxyl group at C-12 and an extra methyl group at the 13-OH. The configuration of C-19 of these compounds was determined to beRusing Mosher's method. A putative biosynthetic gene cluster for compounds1-5was discovered by analyzing the genome ofS. roseumNo. 79089. This 38.6-kb gene cluster contains 38 open reading frames, including a minimal polyketide synthase (wsaA-C), an aromatase (wsaD), three cyclases (wsaE,F, andW), and a series of tailoring enzymes such as monooxygenases (wsaO1-O7) and methyltransferases (wsaM1andM2). Disruption of the ketosynthase gene (wsaA) in this gene cluster abolished the production of1-5, confirming that this gene cluster is indeed responsible for the biosynthesis of1-5. A type II polyketide biosynthetic pathway was proposed for this group of natural endothelin-converting enzyme inhibitors.