Reprogramming the Biosynthesis of Precursor Peptide to Create a Selenazole-Containing Nosiheptide Analogue

ACS Synth Biol. 2022 Jan 21;11(1):85-91. doi: 10.1021/acssynbio.1c00578. Epub 2022 Jan 10.


Nosiheptide (NOS), a potent bactericidal thiopeptide, belongs to a class of natural products produced by ribosomal synthesis and post-translational modifications, and its biosynthetic pathway has largely been elucidated. However, the central trithiazolylpyridine structure of NOS remains inaccessible to structural changes. Here we report the creation of a NOS analogue containing a unique selenazole ring by the construction of an artificial system in Streptomyces actuosus ATCC25421, where the genes responsible for the biosynthesis of selenoprotein from Escherichia coli and the biosynthetic gene cluster of NOS were rationally integrated to produce a selenazole-containing analogue of NOS. The thiazole at the fifth position in NOS was specifically replaced by a selenazole to afford the first selenazole-containing "unnatural" natural product. The present strategy is useful for structural manipulation of various RiPP natural products.

Keywords: RiPPs; genetic code expansion; natural products; selenazole; selenocysteine; synthetic biology.