Understanding the biosynthesis of halogenated nucleosides from Streptomycetes

Abstract

Nucleocidin and dealanylascamycin are two halogenated nucleoside antibiotics produced by Streptomyces calvus and Streptomyces sp. JCM9888, respectively. They share an identical 5’-O-sulfamoyl ribose moiety, but nucleocidin has a fluorine atom on the ribose, while dealanylascamycin has a chlorine atom on the adenine ring. This suggests a common biosynthetic gene cluster for sulfamoylation, but the halogenases responsible for fluorination and chlorination may differ. Although putative biosynthetic gene clusters (BGCs) for dealanylascamycin and nucleocidin were identified through genome mining, the complete biosynthetic pathways remained unresolved.

In Streptomyces sp. JCM9888, additional chlorinated and brominated natural products were elucidated, suggesting that the halogenase responsible for dealanylascamycin is both a chlorinase and a brominase. The precursor of dealanylascamycin was identified and confirmed by gene inactivation, shedding light on a partial biosynthetic pathway.

The putative nucleocidin BGC was found in other Streptomyces strains via genome mining, and Streptomyces virens and Streptomyces aureorectus were confirmed as nucleocidin producers. Additionally, a new fluorometabolite, 4’-fluoroadenosine, was identified in both extracts.

When the putative nucleocidin BGC was heterologously expressed in other Streptomyces type strains, no related natural products were produced. This suggests that the putative BGC is incomplete, prompting further exploration of the functions of genes outside the BGC.