Divergent Pathways in Bisindole Biosynthesis

While the studies presented in this Review do clarify the biosynthetic construction of some bisindole natural products, a number of unusual bisindole molecules are unlikely to be constructed via the same types biosynthetic pathways. For instance, although the molecule nortopsentin A 30 () () appears to have a similar core skeleton to that of violacein, nortopsentin A must be generated through an alternate process: unlike violacein, whose biosynthesis involves loss of a nitrogen, nortopsentin A contains two nitrogens in its central ring. Other molecules (), including ancorinazole 31 (), the cytotoxin cladoniamide G 32 (), the DNA intercalating agent fascaplysin 33 (; ), tjipanazole I 34 (), rhopaladin A 35 (), and the cytotoxin iheyamine B 36 (), whose indole rings may be derived from L-tryptophan, are likely to be generated by yet-unexplored pathways (). A recent, exciting result is the finding that spontaneous oxidative reaction between L-tryptophan and indole-3-pyruvate is responsible for the production of a variety of pigments including pityriacitrin 37 (). Inactivation of the Tam1 gene, which encodes an L-tryptophan aminotransferase in the plant pathogen Ustilago maydis, abolishes production of each of these pigments (). Many of the pigments, including pitriacitrin 37, can be produced, however, by simply incubating the product of Tam1 catalysis, indole-3-pyruvate, with L-tryptophan () (). This unexpected discovery suggests that spontaneous chemistry, already thought to play a role in key steps of indolo[2,3-a]pyrrolo[3,4-c]carbazole, violacein, and bisindolylquinone biosynthesis, can be primarily responsible for production of a series of bisindole pigments. The specific routes to spontaneous production of these pigments should be a rich area for future study, and it is tempting to speculate that spontaneous chemistry may play a role in production of a variety of yet-unexplored bisindole biosynthetic pathways.

Divergent Pathways in the does Biosynthesis of Bisindole Natural Products

Additional opportunities for dimerization and cyclization emerge via formation of indole 3-pyruvate from L-tryptophan. As exemplified by the terrequinone A biosynthetic cluster, tethering of the carboxylate of indole-3-pyruvate as a thioester on a carrier protein generates an electrophile at the carbonyl carbon, which can be subjected to nucleophilic attack by another indole-3-pyruvate molecule (). Hence, the rich chemistry of L-tryptophan provides a template for production of a diversity of bisindole natural products.


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26/08/2015 · Divergent pathways in bisindole biosynthesis

Like other indole alkaloids (), naturally occurring bisindoles are generally thought to be derived from the amino acid L-tryptophan (), and this assumption has indeed proven true for all characterized bisindole biosynthetic pathways. L-tryptophan provides an excellent scaffold for dimerization and derivatization, and consequent production of bisindole molecules which, via distinct chemical properties, give rise to distinct biological properties.