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Published on: August 6, 2018
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Discovery of Partner Protein-Dependent Graspetide Biosynthesis
Riley S Carter1, Sangeetha Ramesh2, Hamada Saad3
1Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
ACS Chemical Biology
|March 14, 2026
Summary
This study reveals novel graspetide biosynthesis pathways dependent on partner proteins, uncovering unique macrocyclic structures and enzymatic modifications. These findings expand the known diversity of ribosomally synthesized and post-translationally modified peptides (RiPPs).
Area of Science:
- Biochemistry and Molecular Biology
- Natural Product Discovery
- Bioinformatics
Background:
- Graspetides are ribosomally synthesized and post-translationally modified peptides (RiPPs) with potential for complex macrocyclic structures.
- Many predicted graspetide biosynthetic gene clusters (BGCs) harbor undiscovered tailoring enzymes capable of modifying peptide scaffolds.
- Existing knowledge of graspetide biosynthesis lacks examples of partner protein dependency and novel cyclization strategies.
Purpose of the Study:
- To investigate graspetide biosynthetic gene clusters (BGCs) for novel tailoring enzymes and biosynthetic pathways.
- To discover new graspetide structures and understand their unique biosynthesis, including partner protein involvement.
- To enhance bioinformatic tools for identifying diverse graspetides and associated tailoring enzymes.
Main Methods:
- Updated the RODEO bioinformatic tool to identify graspetides and associated tailoring enzymes.
- Generated a dataset of over 20,000 predicted graspetides for large-scale bioinformatic analysis.
- Prioritized and characterized two novel graspetide BGCs with conserved co-occurring proteins using in vitro biochemical assays.
Main Results:
- Discovered the first examples of partner protein-dependent graspetide biosynthesis.
- Identified unprecedented cyclized 5-hydroxyisopeptide moieties in graspetides.
- Characterized rosaritide with three interlocking macrolactone linkages and corallotide with five repeated motifs and a novel hydroxylation step.
- Demonstrated that rosaritide synthetase activity and stability depend on a copurifying partner protein.
Conclusions:
- This study significantly expands the known repertoire of graspetide biosynthesis, revealing novel structural features and enzymatic mechanisms.
- The findings highlight the crucial role of partner proteins in the biosynthesis of certain complex RiPPs.
- The enhanced bioinformatic approach and in vitro characterization provide a foundation for future discovery of diverse graspetides.
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