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Expanding the Chemical Space of Synthetic Cyclic Peptides Using a Promiscuous Macrocyclase from Prenylagaramide Biosynthesis
- Source :
- ACS Catal
- Publication Year :
- 2020
- Publisher :
- American Chemical Society (ACS), 2020.
-
Abstract
- Cyclic peptides are excellent drug candidates, placing macrocyclization reactions at the apex of drug development. PatG and related dual-action proteases from cyanobactin biosynthesis are responsible for cleaving off the C-terminal recognition sequence and macrocyclizing the substrate to provide cyclic peptides. This reaction has found use in the enzymatic synthesis of diverse macrocycles. However, these enzymes function best on substrates that terminate with the non-proteinogenic thiazole/thiazoline residue, complicating synthetic strategies. Here, we biochemically characterize a new class of PatG-like macrocyclases that natively use proline, obviating the necessity of additional chemical or biochemical steps. We experimentally define the biochemical steps involved in synthesizing the widespread prenylagaramide-like natural products, including macrocyclization and prenylation. Using saturation mutagenesis, we show that macrocyclase PagG and prenyltransferase PagF are highly promiscuous, producing a library of more than 100 cyclic peptides and their prenylated derivatives in vitro. By comparing our results to known cyanobactin macrocyclase enzymes, we catalog a series of enzymes that collectively should synthesize most small macrocycles. Collectively, these data reveal that, by selecting the right cyanobactin macrocyclase, a large array of enzymatically synthesized macrocycles are accessible.
- Subjects :
- Proteases
Stereochemistry
Prenyltransferase
010402 general chemistry
01 natural sciences
Article
Catalysis
chemistry.chemical_compound
Recognition sequence
Prenylation
Biosynthesis
Saturated mutagenesis
Peptide library
chemistry.chemical_classification
010405 organic chemistry
Thiazoline
General Chemistry
Enzymatic synthesis
Cyclic peptide
Chemical space
0104 chemical sciences
Apex (geometry)
chemistry
Drug development
Biochemistry
Function (biology)
Subjects
Details
- ISSN :
- 21555435
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- ACS Catalysis
- Accession number :
- edsair.doi.dedup.....2d8f58fa7bb60a644942052206598168