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Leader Peptide-Free In Vitro Reconstitution of Microviridin Biosynthesis Enables Design of Synthetic Protease-Targeted Libraries
- Microviridins are a family of ribosomally synthesized and post-translationally modified peptides with a highly unusual architecture featuring non-canonical lactone as well as lactam rings. Individual variants specifically inhibit different types of serine proteases. Here we have established an efficient in vitro reconstitution approach based on two ATP-grasp ligases that were constitutively activated using covalently attached leader peptides and a GNAT-type N-acetyltransferase. The method facilitates the efficient in vitro one-pot transformation of microviridin core peptides to mature microviridins. The engineering potential of the chemo-enzymatic technology was demonstrated for two synthetic peptide libraries that were used to screen and optimize microviridin variants targeting the serine proteases trypsin and subtilisin. Successive analysis of intermediates revealed distinct structure-activity relationships for respective target proteases.
Author details: | Emmanuel Reyna-González, Bianca Schmid, Daniel Petras, Roderich D. Süssmuth, Elke DittmannORCiDGND |
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DOI: | https://doi.org/10.1002/anie.201604345 |
ISSN: | 1433-7851 |
ISSN: | 1521-3773 |
Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/27336908 |
Title of parent work (English): | Angewandte Chemie : a journal of the Gesellschaft Deutscher Chemiker ; International edition |
Publisher: | Wiley-VCH |
Place of publishing: | Weinheim |
Publication type: | Article |
Language: | English |
Year of first publication: | 2016 |
Publication year: | 2016 |
Release date: | 2020/03/22 |
Tag: | biosynthesis; cyanobacteria; microviridins; natural products; peptides |
Volume: | 55 |
Number of pages: | 4 |
First page: | 9398 |
Last Page: | 9401 |
Funding institution: | German Research foundation [Di910/7-1]; Cluster of Excellence, Unifying Concepts in Catalysis (UniCat) by the German Research Council (DFG) |
Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
Peer review: | Referiert |