Understanding the Biosynthesis of SF2575: A Potent Antitumor Compound with Novel Modes of Action

摘要

SF2575 is a tetracycline polyketide produced by Streptomyces sp. SF2575 and displays exceptionally potent anticancer activity. The structure is chemically complex and contains unusual angelate and salicylate tailoring groups. In this study, we identified, sequenced and functionally analyzed the ssf biosynthetic gene cluster. Intermediates were isolated from the SF2575 culture extract to suggest the order of pendant groups addition is C-9 glycosylation, C-4 salicylation and C-4' angelycylation. Cytotoxicity studies demonstrated loss of activity following removal of angelate and further inactivity following loss of salicylate indicating that both acyl groups are critical to the potent bioactivity. Two enzymes responsible for C-4 acylation of salicylate were identified and characterized in vitro, an ATP-dependent salicylyl-CoA ligase SsfL1 and acyltransferase SsfX3. Understanding the biosynthesis of SF2575 can therefore expand the repertoire of enzymes that can modify tetracyclines, and facilitate engineered biosynthesis of SF2575 analogs.