Incorporation of Non-canonical Amino Acids into 2,5- Diketopiperazines by Cyclodipeptide Synthases

The manipulation of natural product biosynthetic pathways is a powerful means of expanding the chemical diversity of bioactive molecules. 2,5-diketopiperazines (2,5- DKPs) have been widely developed by medicinal chemists, but their biological production is yet to be exploited. We introduce an in vivo method for incorporating non-canonical amino acids (ncAAs) into 2,5-DKPs using cyclodipeptide synthases (CDPSs), the enzymes responsible for scaffold assembly in many 2,5-DKP biosynthetic pathways. CDPSs use aminoacyl- tRNAs as substrates. We exploited the natural ability of aminoacyl-tRNA synthetases to load ncAAs onto tRNAs. We found 26 ncAAs to be usable as substrates by CDPSs, leading to the enzymatic production of approximately 200 non-canon- ical cyclodipeptides. CDPSs constitute an efficient enzymatic tool for the synthesis of highly diverse 2,5-DKPs. Such diversity could be further expanded, for example, by using various cyclodipeptide-tailoring enzymes found in 2,5-DKP biosynthetic pathways.

 

References:
Incorporation of Non-canonical Amino Acids into 2,5- Diketopiperazines by Cyclodipeptide Synthases
Nicolas Canu, Pascal Belin, Robert Thai, Isabelle Correia, Olivier Lequin, JÿrÙme Seguin, Mireille Moutiez,* and Muriel Gondry*
Angew. Chem. Int. Ed. 2018, 57, 3118 –3122
DOI: 10.1002/anie.201712536