Aspartimide Modification in RiPP Natural Products

Area of Science:

• Biochemistry
• Molecular Biology
• Peptide Chemistry

Background:

• Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a diverse class of natural products.
• An enigmatic functional group, the aspartimide, is found in multiple RiPP classes.
• Enzymes related to protein isoaspartyl methyltransferase (PIMT) catalyze aspartimide formation.

Purpose of the Study:

• To elucidate the biochemical details of aspartimidylation in known RiPP classes.
• To discover and characterize novel RiPPs featuring aspartimide modification.
• To identify knowledge gaps and suggest future research directions in RiPP modification.

Main Methods:

• Biochemical characterization of aspartimidylation pathways.
• Enzyme assays and kinetic studies.
• Bioinformatic analysis and discovery of new RiPPs.

Main Results:

• Detailed biochemical mechanisms of aspartimidylation were described for lanthipeptides, lasso peptides, and graspetides.
• A novel class of RiPPs, termed imiditides (or type I pamtides), was discovered.
• Aspartimide was identified as the defining post-translational modification for imiditides.

Conclusions:

• RiPP-associated PIMTs exhibit distinct substrate specificity compared to canonical PIMTs.
• The discovery of imiditides expands the known diversity of RiPPs and their modifications.
• Further research is needed to fully understand the biological roles and catalytic mechanisms of aspartimidylating enzymes.