Unprecedented Biological Cyclopropanation In The Biosynthesis Of Fr-900848

摘要

We were able to show the predominant incorporation of a single enantiomer and intact incorporation of multiply labelled synthetic diketide precursors (14 and 16), which established the intermediacy of eyclopropanated diketide and led to our proposal for the unprecedented biological cyclopropanation, via PKS (polyketide synthase) having a novel cyclopropanase domain, in the biosynthesis of FR-900848 (1).rnFR-900848 (1) is a polyketide-nucleoside produced by Streptoverticillium fervens HP-891 and shows potent activity against phytopathogenic fungi. Its structure consists of a cyclopropanated fatty acid containing one isolated and four contiguous cyclopropanes, and 5"-amino-5"-deoxy-5',6'-di-hydrouridine (Fig. 1). The closely related compound U-106305 (3), an inhibitor of the cholesteryl ester transfer protein (CETP), was isolated from Streptomyces sp. UC 11136 by Kuo et al and was found to have the same absolute stereochemistry for cyclopropane rings. To elucidate the mechanism for enzymatic construction of polycyclopropanes, we have started on a biosynthetic study of FR-900848 (1) and determined its biosynthetic building units by a series of feeding experiments with isotopically labelled precursors. These results established that the backbone of 1 was constructed via a polyketide pathway and was coupled with an amino-nucleoside unit derived from dihydrouridine. In addition, methylenes of the most characteristic cyclopropane moieties in 1 were derived from L-methionine.