Discovery and Biosynthetic Studies of a Highly Reduced Cinnamoyl Lipid, Tripmycin A, from an Endophytic Streptomyces sp.

A Tripterygium wilfordii endophyte, Streptomyces sp. CB04723, was shown to produce an unusually highly reduced cytotoxic cinnamoyl lipid, tripmycin A ( 1 ). Structure-activity relationship studies revealed that both the cinnamyl moiety and the saturated fatty acid side chain are indispensable to the over 400-fold cytotoxicity improvement of 1 against the triple-negative breast cancer cell line MDA-MB-231 compared to 5-(2-methylphenyl)-4-pentenoic acid ( 2 ). Bioinformatical analysis, gene inactivation, and overexpression revealed that Hxs15 most likely acted as an enoyl reductase and was involved with the side chain reduction of 1 , which provides a new insight into the biosynthesis of cinnamoyl lipids.