Discovery of the Showdomycin Gene Cluster from <i>Streptomyces showdoensis</i> ATCC 15227 Yields Insight into the Biosynthetic Logic of C‑Nucleoside Antibiotics

Nucleoside antibiotics are a large class of pharmaceutically relevant chemical entities, which exhibit a broad spectrum of biological activities. Most nucleosides belong to the canonical N-nucleoside family, where the heterocyclic unit is connected to the carbohydrate through a carbon–nitrogen bond. However, atypical C-nucleosides were isolated from <i>Streptomyces</i> bacteria over 50 years ago, but the molecular basis for formation of these metabolites has been unknown. Here, we have sequenced the genome of <i>S. showdoensis</i> ATCC 15227 and identified the gene cluster responsible for showdomycin production. Key to the detection was the presence of <i>sdmA</i>, encoding an enzyme of the pseudouridine monophosphate glycosidase family, which could catalyze formation of the C-glycosidic bond. Sequence analysis revealed an unusual combination of biosynthetic genes, while inactivation and subsequent complementation of <i>sdmA</i> confirmed the involvement of the locus in showdomycin formation. The study provides the first steps toward generation of novel C-nucleosides by pathway engineering