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Exclusive production of fluoro-unnatural oxindole alkaloids by transgenic Uncaria guianensis via precursor-directed biosynthesis


Natural product derivatives or "unnatural products" are known to play a substantial role in drug discovery. Nowadays, there are about 200 pharmaceuticals fluorine containing into various heterocyclic scaffolds and the presence of fluorine atoms within their structures increase the therapeutic efficacy and pharmacological properties. Metabolic engineering strategies to generate "unnatural" monoterpene indole alkaloids have been successful in medicinal plant Catharanthus roses by Dr. Sarah E. O'Connor's Lab, John Innes Centre, and UK. Mutasynthesis strategies mediated by RNA suppression of tryptamine biosynthesis in Catharanthus roses eliminated production of natural monoterpene indole alkaloids and it was possible to obtain desirable unnatural alkaloid production by supplementation with unnatural tryptamine analogues. Uncaria guianensis biosynthesize oxindole alkaloids, which are known to have biological significance, by the same biosynthetically route as found in vinca alkaloids (Catharanthus roseus). Our goal is carry out RNA silencing of tryptophan decarboxylase (TDC) to suppress the biosynthesis of tryptamine in Uncaria guianensis (Rubiaceae) callus culture in order to obtain novel fluoro-unnatural oxindole alkaloids. The combination of genetic manipulation and precursor-directed biosynthesis using unnatural precursors (fluoro-tryptamine) represents an increasingly viable resource to produce unnatural oxindole alkaloids into transgenic callus culture from U. guianensis. (AU)

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