Interfacing a phosphate catalytic reaction with a microbial metabolism for the production of azaphilone alkaloids

Synthetic biology is becoming a conventional technique to maximize the production of interesting small molecule chemicals. However, it remains difficult to find the corresponding gene encoding enzymes for the biosynthesis of most new natural products or non-natural products. Many strategies, such as designing non-natural enzymes or artificial enzymes, have been tried to cross the boundary of microbial metabolism. Herein, PO43− as a Brønsted acid catalyst is explored to catalyze the chemical reaction between azaphilones (a subgroup of fungi polyketides) and amines under mild conditions. We further demonstrate that the mild chemical reaction is biocompatible and can be directly interfaced with the microbial metabolism of azaphilones. The combination of chemo- and biosynthesis into a one-pot process in a simple way exhibits many advantages, such as diversifying natural azaphilone alkaloids, eliminating possible product inhibition or degradation, and acting as a novel strategy for sustainable chemistry.