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Tryptophan-Centric Bioinformatics Identifies New Lasso Peptide Modifications.
Lonnie A Harris1, Hamada Saad1, Kyle E Shelton1
1Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
Biochemistry
|March 18, 2024
Summary
Researchers discovered new tryptophan modifications in lasso peptides using a bioinformatics strategy. This approach identified novel enzymes and peptide structures, advancing our understanding of these complex molecules.
Area of Science:
- Biochemistry
- Molecular Biology
- Bioinformatics
Background:
- Lasso peptides are ribosomally synthesized and post-translationally modified peptides (RiPPs) characterized by a unique macrolactam linkage and a threaded rotaxane conformation.
- Advances in bioinformatics have revealed an increasing diversity of secondary modifications in lasso peptides.
- Discovering novel ancillary modifications is crucial for understanding lasso peptide diversity and function.
Purpose of the Study:
- To develop a targeted bioinformatic strategy for discovering new lasso peptides with modifications to tryptophan (Trp).
- To identify novel ancillary modifying enzymes acting on Trp residues within lasso peptide biosynthetic gene clusters.
- To characterize newly identified Trp-modified lasso peptides and their associated enzymes.
Main Methods:
- Development of a bioinformatic strategy focused on identifying Trp-rich precursor peptides in lasso peptide gene clusters.
- Bioinformatic parsing of identified gene clusters to uncover putative ancillary modifying enzymes, including halogenases and dimethylallyltransferases.
- Biochemical characterization of gene products to confirm enzymatic activity and identify novel peptide modifications.
Main Results:
- Identification of numerous putative lasso peptide biosynthetic gene clusters enriched in Trp.
- Discovery of several putative ancillary modifying enzymes, such as halogenases and dimethylallyltransferases, targeting Trp.
- Characterization of two novel lasso peptides: chlorolassin with two 5-Cl-Trp modifications and wygwalassin with 5-dimethylallyl-Trp and 2,3-didehydro-Tyr modifications.
Conclusions:
- A Trp-centric bioinformatic strategy is effective for discovering novel ancillary modifications in lasso peptides.
- This approach has led to the identification of new Trp-modified lasso peptides and their biosynthetic enzymes.
- The strategy holds potential for discovering ancillary modifications in other RiPP classes and predicting enzyme functions.
