Macrocyclization and Backbone Modification in RiPP Biosynthesis.

Area of Science:

• Biochemistry and Natural Products Chemistry
• Molecular Biology and Peptide Synthesis

Background:

• Significant progress in understanding ribosomally synthesized and posttranslationally modified peptides (RiPPs) over the last decade.
• Macrocyclization is a key modification in RiPPs, also utilized in medicinal chemistry for enhanced drug properties.
• Peptide backbone modifications, including amide alterations, are observed in RiPP biosynthesis.

Purpose of the Study:

• To review the molecular mechanisms governing the biosynthesis of specific macrocyclic RiPP families.
• To highlight unusual biochemical strategies employed in RiPP cyclization and modification.
• To discuss novel pathways for small molecule generation via posttranslational modification.

Main Methods:

• Focus on five classes of lanthipeptides, sactipeptides, ranthipeptides, thiopeptides, and streptides.
• Detailed examination of cyclization mechanisms: Michael-type addition, radical chemistry, [4+2] cycloaddition, and radical C-C bond formation.
• Analysis of posttranslational modifications: backbone amide methylation, epimerization, and thioamide formation.

Main Results:

• Elucidation of diverse thioether and carbon-carbon bond-forming strategies in RiPP macrocyclization.
• Characterization of unique enzymatic pathways for peptide backbone modifications.
• Identification of an unconventional route to small molecules through posttranslational processing.

Conclusions:

• The biosynthesis of macrocyclic RiPPs involves a remarkable array of sophisticated enzymatic transformations.
• Understanding these complex mechanisms provides insights into natural product drug discovery and peptide engineering.
• Posttranslational modification pathways offer novel strategies for generating structurally diverse small molecules.