Enzymatic Benzofuranoindoline Formation in the Biosynthesis of the Strained Bridgehead Bicyclic Dipeptide (+)-Azonazine A

We uncovered and reconstituted a concise biosynthetic pathway of the strained dipeptide (+)-azonazine A from marine-derived Aspergillus insulicola. Formation of the hexacyclic benzofuranoindoline ring system from cyclo-(L-Trp-N-methyl-L-Tyr) is catalyzed by a P450 enzyme through an oxidative cyclization. Supplementing the producing strain with various indole-substituted tryptophan derivatives resulted in the generation of a series of azonazine A analogs.

Automated summary

We have discovered and reconstructed a concise biosynthetic pathway of the strained dipeptide (+)-azonazine A using Aspergillus insulicola from marine sources. A P450 enzyme catalyzes the formation of the hexacyclic benzofuranoindoline ring system from cyclo-(L-Trp-N-methyl-L-Tyr) through oxidative cyclization. Supplementing the producing strain with different indole-substituted tryptophan derivatives resulted in the production of a series of azonazine A analogs.