Aza-Tryptamine Substrates in Monoterpene Indole Alkaloid Biosynthesis

Abstract

Biosynthetic pathways can be hijacked to yield novel compounds by introduction of novel starting materials. Here we have altered tryptamine, which serves as the starting substrate for a variety of alkaloid biosynthetic pathways, by replacing the indole with one of four aza-indole isomers. We show that two aza-tryptamine substrates can be successfully incorporated into the products of the monoterpene indole alkaloid pathway in Catharanthus roseus. Use of unnatural heterocycles in precursor directed biosynthesis, in both microbial and plant natural product pathways, has not been widely demonstrated, and successful incorporation of starting substrate analogs containing the aza-indole functionality has not been previously reported. This work serves as a starting point to explore fermentation of aza-alkaloids from other tryptophan and tryptamine derived natural product pathways.

The Pictet–Spengler Reaction in Nature and in Organic Chemistry

“…Following optimized overexpression, [57] STR1 was used for the synthesis of azastrictosidine from 7-azatryptamine (Scheme 7). [56,58] Moreover, azastrictosidine has been used for the simple one-step chemical synthesis of a previously unknown lactam of azastrictosidine and for azanacycline under basic and acidic conditions, respectively. [56] Modification of the tryptamine unit by introducing a nitrogen atom in different positions should, therefore, ultimately result in a range of diverse and novel azaindole alkaloids.…”

“…[56] mutant with 5-substituted tryptamine analogues resulted in the production of a variety of substituted alkaloid types (Scheme 8). [58] In a related approach, RNA silencing of tryptamine biosynthesis was used to block alkaloid production in C. roseus roots. Tryptophan decarboxylase, which generates tryptamine, was blocked.…”

Merging Chemical Synthesis and Biosynthesis: A New Chapter in the Total Synthesis of Natural Products and Natural Product Libraries

“…An elegant example from the field of mixed terpenealkaloid synthesis that relies on chemical synthesis followed by a two-step enzymatic transformation protocol and a fermentation is shown in Scheme 10. [33] 7-Aza-tryptamine 50 obtained from pyridyl bromide 49 by chemical synthesis was subjected to a two-step biotransformation based on recombinant stricdosidine synthase and strictosidine glycosidase to yield advanced precursor 53 via intermediate 52. [34] Stricdosidine synthase requires secologanine (51), which was obtained by fermentation.…”

Formation of a Novel Macrocyclic Alkaloid from the Unnatural Farnesyl Diphosphate Analogue Anilinogeranyl Diphosphate by 5-Epi-Aristolochene Synthase

“…19 We report here the efficient formation of a 13-membered macrocycle alkaloid 3,7-dimethyl- trans,trans -3,7-aza[9]paracyclophane-diene “geraniline” via a carbon–carbon bond forming cyclization of AGPP catalyzed by the tobacco 5-epi-aristolochene synthase. This report highlights the utility of enzymatic cyclization approaches for the generation of medium sized ring systems under mild conditions of aqueous incubations at RT.…”