Complexity generation in fungal indole alkalod biosynthesis

Communesins are a group of indole alkaloids, bearing a unique cage-like heptacyclic scaffold, isolated from various marine and terrestrial Penicillium spp. Due to their structural novelty and potential as pharmaceutical and insecticidal agents, this family of compounds has inspired numerous total synthesis efforts in recent years. However, the genetic and biochemical basis of communesin biosynthesis have remained unexplored.  Here, we report the identification and characterization of the communesins biosynthetic gene cluster from Penicillium expansum. We confirmed the pathway involved in the formation of aurantioclavine together with the post-modification steps including methylation, epoxidation and acylation by targeted-gene deletion experiments and structural elucidation of the isolated intermediates. We show that the precursors of communesin tryptamine and aurantioclavine, are generated from two divergent pathways from L-tryptophanm using chemical complementation studies. The coupling of these two indole building blocks to yield the heptacyclic core in communesin involves minimally a P450 monooxygenase.  Our studies uncovered the biosynthetic mystery surrounding this famous indole alkaloid, and set the stages for detailed biochemical characterization to understand how nature generates exceptional structural complexity from simple building blocks.