FD-891 is a 16-membered antibiotic macrolide, which is especially active against human leukemia such as HL-60 and Jurkat cells. In the present study, we found that FD-891 triggers caspase-8-dependent mitochondrial release of cytochrome c and subsequent qpoptosis in Jurkat cells. Also, the molecular target of FD-891 was found to be actin to inhibit the binding with actin-binding proteins on cell membrane causing aggregation of actin. We further identified the FD-891 biosynthetic (gfs) gene cluster from the producer Streptomyces graminofaciens A-8890 to prepare FD-891 analogs with biosynthetic technology. The identified gfs gene cluster contains five modular type I PKS genes (gfsA, B, C, D and E), a cytochrome P450 gene (gfsF) and a methyltransferase gene (gfsG). The gene organization of PKS agreed well with the basic polyketide skeleton of FD-891 indicating its involvement in the FD-891 boisynthesis. The gfsF and gfsG gene inactivation resulted in the loss of FD-891 production; instead, the gfsF gene disrupted mutant accumulated a novel FD-891 analog 25-O-methyl FD-892, which lacked an epoxide and a hydroxyl group of FD-891, and the gfsG gene disrupted mutant accumulated another analog 25-O-demethyl FD-891. Biochemical studies of the newly created FD-891 analogs will be also discussed.
