Bacterial cyclophane-containing RiPPs from radical SAM enzymes

Area of Science:

• Biochemistry
• Natural Product Chemistry
• Synthetic Biology

Background:

• Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a diverse class of natural products.
• Cyclophane-containing RiPPs, particularly bacterial monoaryl variants, have gained recent attention.
• These RiPPs are biosynthesized by radical SAM/SPASM enzymes.

Purpose of the Study:

• To highlight bacterial monoaryl cyclophane-containing RiPPs and their biosynthetic pathways.
• To review discovery approaches, enzyme mechanisms, and synthetic methods.
• To underscore their potential in drug discovery and synthetic biology.

Main Methods:

• Natural product-first discovery strategies.
• Enzyme-first discovery strategies.
• Analysis of enzyme mechanisms and synthetic pathway reconstruction.

Main Results:

• Identification of diverse cyclophane ring systems in bacterial RiPPs.
• Demonstration of antibacterial activity against gram-negative pathogens.
• Characterization of radical SAM/SPASM enzymes responsible for cyclophane formation.

Conclusions:

• Bacterial monoaryl cyclophane-containing RiPPs are a promising source of novel bioactive compounds.
• The biosynthetic enzymes offer valuable tools for synthetic biology applications.
• These scaffolds represent an untapped resource for future drug discovery efforts.