期刊
ACS CATALYSIS
卷 10, 期 13, 页码 7146-7153出版社
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.0c00623
关键词
ribosomally synthesized and post-translationally modified peptides; RiPPs; post-translational modification; enzymatic synthesis; peptide library; natural products
资金
- NIH [GM122521]
- Skaggs Graduate Research Fellowship
Cyclic peptides are ubiquitous 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 nonproteinogenic thiazole/thiazoline residue, complicating synthetic strategies. Here, we biochemically characterize an additional 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 macrocyclases, we catalog a series of enzymes from this family that 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.
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