Nonribosomal peptides (NRPs) that are synthesized by modular megaenzymes known as nonribosomal peptide synthetases (NRPSs) are a rich source for drug discovery. By targeting an unusual NRPS architecture, we discovered an unusual biosynthetic gene cluster (bsm) from Streptomyces sp. 120454 and identified that it was responsible for the biosynthesis of a series of novel linear peptides, bosamycins. The bsm gene cluster contains a unique monomodular NRPS, BsmF, that contains a cytochrome P450 domain at the N-terminal. BsmF (P450 + A + T) can selectively activate tyrosine with its adenylation (A) domain, load it onto the thiolation (T) domain, and then hydroxylate tyrosine to form 5-OH tyrosine with the P450 domain. We demonstrated a NRPS assembly line for the formation of bosamycins by genetic and biochemical analysis and heterologous expression. Our work reveals a genome mining strategy targeting a unique NRPS domain for the discovery of novel NRPs.
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