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Constructing Cyclic Peptides Using an On-Tether Sulfonium Center
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Cyclic peptide production using a macrocyclase with enhanced substrate promiscuity and relaxed recognition
Cristina N Alexandru-Crivac1, Christian Umeobika2, Niina Leikoski3
1Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, UK. l.trembleau@abdn.ac.uk w.houssen@abdn.ac.uk and Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.
Chemical Communications (Cambridge, England)
|September 15, 2017
Summary
A new enzyme expands macrocyclic peptide synthesis. This novel cyanobactin macrocyclase broadens substrate scope, enabling the creation of diverse therapeutic peptides beyond current limitations.
Area of Science:
- Biochemistry
- Synthetic Biology
- Medicinal Chemistry
Background:
- Macrocyclic peptides show therapeutic promise but face synthetic challenges.
- Existing cyanobactin macrocyclases like PatGmac have limitations in substrate length and composition (6-11 amino acids, requiring proline/thiazoline).
Purpose of the Study:
- To engineer a novel cyanobactin macrocyclase with an expanded substrate scope.
- To overcome limitations of existing enzymes for macrocyclic peptide production.
Main Methods:
- Enzyme engineering and directed evolution (details not provided in abstract).
- Testing the new macrocyclase activity on various peptide substrates.
Main Results:
- A new cyanobactin macrocyclase capable of cyclizing longer peptide substrates (beyond 11 amino acids) was developed.
- The enzyme successfully cyclizes substrates lacking proline or thiazoline residues.
- This expands the chemical diversity accessible through enzymatic macrocyclization.
Conclusions:
- The engineered macrocyclase significantly broadens the utility of enzymatic synthesis for diverse macrocyclic peptides.
- This advancement facilitates the exploration and production of novel peptide therapeutics.
