Genome Mining of Fungal Aza-Polycyclic Natural Products Derived from Arginine-Containing Cyclodipeptides

Arginine-containing cyclodipeptide synthases (RCDPSs)
from fungi
constitute a new family of tRNA-dependent enzymes that can biosynthesize
cyclo-Arg-Xaa dipeptides. The incorporation of an arginine residue
significantly expands the chemical space of guanidine-containing natural
products. Here, we mined fungal biosynthetic gene clusters (BGCs)
containing different RCDPS to discover aza-polycyclic natural products.
The pno BGC from Aspergillus pseudonomius produced pentacyclic pyrroloindoline diketopiperazines (DKPs) of
which the arginine side chain is oxidatively cyclized into a guanidino-proline.
Two RCDPS-encoding BGCs, car and esh from Aspergillus carlsbadensis and Eupenicillium
shearii, respectively, produced DKPs connected to five- and
seven-membered spirocycles as a result of oxidative cyclization of
the guanidino group catalyzed by α-ketoglutarate/Fe­(II)-dependent
oxygenases. The esh pathway involves a tandem cyclization
and epimerization to generate the guanidino-bridged tricyclo-[3.31,2.2.2]-piperazinedione core. The aza-polycyclic structures
characterized in this work demonstrate the potential of using RCDPS
as a starting point for the discovery of new natural products.