RESEARCH ARTICLE Expanding our Understanding of Sequence- Function Relationships of Type II Polyketide Biosynthetic Gene Clusters: Bioinformatics- Guided Identification of Frankiamicin A from

A large and rapidly increasing number of unstudied “orphan ” natural product biosynthetic gene clusters are being uncovered in sequenced microbial genomes. An important goal of modern natural products research is to be able to accurately predict natural product struc-tures and biosynthetic pathways from these gene cluster sequences. This requires both de-velopment of bioinformatic methods for global analysis of these gene clusters and experimental characterization of select products produced by gene clusters with divergent sequence characteristics. Here, we conduct global bioinformatic analysis of all available type II polyketide gene cluster sequences and identify a conserved set of gene clusters with unique ketosynthase α/β sequence characteristics in the genomes of Frankia species, a group of Actinobacteria with underexploited natural product biosynthetic potential. Through LC-MS profiling of extracts from several Frankia species grown under various conditions, we identified Frankia sp. EAN1pec as producing a compound with spectral characteristics consistent with the type II polyketide produced by this gene cluster. We isolated the com-pound, a pentangular polyketide which we named frankiamicin A, and elucidated its struc