Summary
Ribosomally Synthesized and Post-Translationally Modified Peptides (RiPPs) are a diverse class of bioactive natural products that originate from gene-encoded precursor peptides. Their biosynthesis relies on a leader peptide sequence that recruits specific enzymes to modify a core peptide segment.
Key Points
- 1RiPPs are gene-encoded peptides modified by post-translational enzymes
- 2Leader peptides recruit modification enzymes while core peptides become the final product
- 3Modifications include lanthionine bridges, thiazole rings, macrolactams, and lasso topologies
- 4Lantibiotics like nisin use thioether crosslinks for antimicrobial activity
- 5RiPP biosynthesis combines ribosomal efficiency with non-ribosomal chemical diversity
RiPPs represent a hybrid biosynthetic strategy that combines the efficiency of ribosomal synthesis with the chemical diversity typically associated with non-ribosomal pathways.
Precursor Peptide Architecture
Two-Part Structure
RiPP precursor peptides consist of:
1. Leader peptide: An N-terminal sequence that recruits modification enzymes but is cleaved in the final product
2. Core peptide: The C-terminal segment that becomes the mature, bioactive product
The leader peptide acts as a recognition element, binding to modification enzymes and positioning the core peptide for catalysis.
Modification Diversity
Post-translational modifications convert simple amino acid sequences into complex, chemically diverse structures:
- Lanthionine bridges: Thioether crosslinks formed in lantibiotics (e.g., nisin)
- Thiazole/oxazole rings: Heterocycles formed from Cys, Ser, or Thr
- Macrolactams: Large ring structures from head-to-tail or side-chain cyclization
- Lasso topologies: Threaded ring-and-tail architectures resistant to proteolysis
Major RiPP Classes
Lantibiotics
Characterized by lanthionine and methyllanthionine thioether bridges. Nisin, the prototypical lantibiotic, is widely used as a food preservative due to its antimicrobial activity against Gram-positive bacteria.
Thiopeptides
Contain thiazole rings and a characteristic six-membered nitrogen heterocycle. Examples include thiostrepton, which inhibits ribosomal translation.
Lasso Peptides
Feature a unique rotaxane-like topology where the C-terminal tail threads through an N-terminal macrolactam ring. This structure confers exceptional stability against proteases and thermal denaturation.
Cyanobactins
Cyclic peptides from cyanobacteria, often containing heterocyclic modifications. Patellamides are examples with metal-binding properties.
Biosynthetic Advantages
Evolvability
Because RiPPs are gene-encoded:
Engineering Potential
RiPPs offer unique opportunities for drug discovery:
- Low metabolic cost: Ribosomal synthesis is energetically efficient
- High diversity: PTM enzymes generate chemical complexity
- Modularity: Leader peptides can be swapped to create chimeric pathways
Therapeutic Applications
RiPPs are sources of: