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Constructing Cyclic Peptides Using an On-Tether Sulfonium Center
Published on: September 28, 2022
Circular logic: nonribosomal peptide-like macrocyclization with a ribosomal peptide catalyst
John A McIntosh1, Charles R Robertson, Vinayak Agarwal
1Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112, USA.
Journal of the American Chemical Society
|October 22, 2010
Summary
A novel protease discovered in ribosomal peptide biosynthesis can macrocyclize various molecules, similar to nonribosomal peptide products. This enzyme utilizes amide bonds, differing from thioesterase mechanisms in its substrate chemistry.
Area of Science:
- Biochemistry
- Molecular Biology
- Enzymology
Background:
- Ribosomal peptide biosynthesis is a fundamental process in cells.
- Nonribosomal peptides and hybrid polyketide-peptide products are complex molecules with diverse biological activities.
- Enzymatic mechanisms for macrocyclization are crucial for generating these complex structures.
Purpose of the Study:
- To identify and characterize a novel protease involved in ribosomal peptide biosynthesis.
- To investigate the substrate scope and catalytic mechanism of this protease.
- To compare its mechanism to known enzymatic pathways like thioesterase catalysis.
Main Methods:
- Enzyme purification and activity assays.
- Substrate synthesis and characterization.
- Kinetic analysis and mechanistic studies.
- Comparison with thioesterase enzymes.
Main Results:
- A protease from ribosomal peptide biosynthesis was identified.
- This protease effectively macrocyclizes a range of substrates.
- Substrates included those mimicking nonribosomal peptide and hybrid polyketide-peptide products.
- The enzyme's mechanism involves amide bond hydrolysis, distinct from thioesterase activity.
Conclusions:
- A novel ribosomal protease capable of macrocyclization has been discovered.
- This enzyme broadens the known repertoire of macrocyclization mechanisms.
- The findings provide insights into the biosynthesis of complex peptides and related natural products.
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