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Peptide Prenylation Follows Divergent Substrate Engagement Rules
Mujeeb A Wakeel1, Andrew C McShan1, Vinayak Agarwal1,2
1School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.
Journal of the American Chemical Society
|December 2, 2025
Summary
Prenylation of lanthipeptides involves recognizing the entire precursor peptide, including the leader region. This differs from other RiPP prenyltransferases, suggesting leader recognition dictates substrate specificity.
Area of Science:
- Biochemistry
- Molecular Biology
- Natural Product Chemistry
Background:
- Lipidation is a key modification for bioactivity in ribosomally synthesized and post-translationally modified peptides (RiPPs).
- Lanthipeptides are a diverse class of RiPPs, and their prenylation is a critical step in their biosynthesis.
Purpose of the Study:
- To investigate the substrate recognition mechanism of lanthipeptide prenyltransferases.
- To compare the prenylation mechanism of lanthipeptides with that of other RiPPs, such as cyanobactins.
Main Methods:
- Biochemical assays to study enzyme kinetics and substrate binding.
- Bioinformatic analysis of prenyltransferase sequences and substrate interactions.
Main Results:
- Lanthipeptide prenyltransferases recognize the complete precursor peptide, including the N-terminal leader region.
- This leader-inclusive recognition contrasts with cyanobactin prenyltransferases, which do not engage the leader peptide.
- Leader peptide recognition confers substrate selectivity on lanthipeptide prenyltransferases.
Conclusions:
- The N-terminal leader region of lanthipeptide precursors plays a crucial role in substrate selectivity for prenyltransferases.
- This mechanism of recognition differs significantly from the leader-free prenylation observed in cyanobactins, leading to distinct substrate scopes.
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