Nucleocidin: lost in 1956, found in 2015.

nucleocidin

Nucleocidin is a rare example of a natural product containing fluorine. Only six structurally distinct examples of fluorinated natural products are known!  (Fun fact: nucleocidin contains an equally rare sulfamate group, shown in red). As a fluorinated analog of adenosine, nucleocidin belongs to a very valuable and pharmaceutically useful category of molecules known as fluorosugars. Such compounds include FMAU (antiviral, anticancer), FLT (anti-HIV), and Gemcitabine (anticancer). The chemistry required to incorporate fluorine into nucleocidin is also intriguing from the perspective of enzyme mechanisms. However, our lab faced a decades old problem if we wanted to study the biosynthesis of nucleocidin: the producing bacterium, Streptomyces calvus, only produced the molecule in the labs of American Cyanamid way back in 1956! The propagated samples of S. calvus that are available in public collections (e.g: ATCC, DSMZ), have invariably failed to produce nucleocidin. We found that this was due to a mutation in a well known gene called bldA. Upon correcting this gene, the genes encoding nucleocidin production were activated, and biosynthesis was restored (see ChemBioChem 2015). Our next target is the enzyme that catalyzes the incorporation of fluorine.

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