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Incorporation of Non‐canonical Amino Acids into 2,5‐Diketopiperazines by Cyclodipeptide Synthases
Author(s) -
Canu Nicolas,
Belin Pascal,
Thai Robert,
Correia Isabelle,
Lequin Olivier,
Seguin Jérôme,
Moutiez Mireille,
Gondry Muriel
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201712536
Subject(s) - diketopiperazines , aminoacyl trna synthetase , amino acid , biosynthesis , chemistry , enzyme , natural product , chemical biology , biochemistry , amino acyl trna synthetases , computational biology , transfer rna , combinatorial chemistry , stereochemistry , biology , rna , gene
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‐canonical 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.