Ribosomally Synthesized and Post-Translationally Modified Peptides (RiPPs)

Summary

RiPPs represent a diverse superfamily of natural products that are biosynthesized through ribosomal translation of a precursor peptide followed by extensive enzymatic modifications. Unlike NRPS products, RiPPs are genetically encoded, allowing for rapid diversification through mutation.

Key Points

1RiPPs are genetically encoded natural products made by ribosomal translation then enzymatic modification
2Precursor peptides contain a leader (for enzyme recognition) and core (becomes product) region
3Major classes include lanthipeptides, thiopeptides, lasso peptides, and cyanobactins
4Post-translational modifications create heterocycles, macrocycles, and unusual crosslinks
5Genetic tractability enables rapid diversification through mutation and genome mining

# Ribosomally Synthesized and Post-Translationally Modified Peptides (RiPPs)

Ribosomally synthesized and post-translationally modified peptides (RiPPs) constitute a rapidly expanding class of natural products characterized by their ribosomal origin and subsequent enzymatic tailoring. This biosynthetic logic combines the efficiency of ribosomal translation with the chemical diversity achievable through post-translational modifications.

Precursor Peptide Architecture

Three-Domain Organization

RiPP precursor peptides typically contain:

- Leader peptide: N-terminal region recognized by modification enzymes

- Core peptide: The region that becomes the mature natural product

- Follower peptide: Optional C-terminal recognition element (in some classes)

Recognition and Processing

Leader peptides contain conserved motifs for enzyme binding

Modification enzymes bind the leader while acting on the core

Proteolytic removal of the leader releases the mature product

Major RiPP Classes

Lanthipeptides (Lantibiotics)

Contain lanthionine and methyllanthionine crosslinks

- Nisin: The prototypical lantibiotic used in food preservation

Formed by dehydration of Ser/Thr followed by Michael addition of Cys

Thiopeptides

Highly modified with a central pyridine/dehydropiperidine macrocycle

- Thiostrepton: Ribosome-targeting antibiotic

Contain multiple thiazole and dehydroamino acid modifications

Lasso Peptides

Unique [1]rotaxane topology with threaded tail through macrolactam ring

Exceptional proteolytic and thermal stability

- Microcin J25: Antibacterial RNA polymerase inhibitor

Cyanobactins

Cyclic peptides from cyanobacteria

Contain heterocycles (thiazoles, oxazoles) and prenyl groups

- Patellamide A: Cytotoxic compound from ascidian symbionts

Sactipeptides

Contain sulfur-to-alpha-carbon (sactionine) crosslinks

Radical SAM enzymes catalyze C-S bond formation

- Subtilosin A: Antimicrobial from Bacillus subtilis

Biosynthetic Logic

Modification Enzyme Classes

| Enzyme Type | Modification | Example |

|-------------|--------------|---------|

| Dehydratases | Ser/Thr → Dha/Dhb | LanB/LanM |

| Cyclases | Thioether formation | LanC/LanM |

| Heterocyclases | Azole formation | YcaO |

| Radical SAM | C-H functionalization | Various |

| Prenyltransferases | Isoprenoid addition | PagF |

The RiPP Precursor Recognition Element (RRE)

Conserved structural domain in modification enzymes

Binds specifically to leader peptide sequences

Positions the core peptide for efficient modification

Evolutionary and Biotechnological Significance

Genetic Tractability

Simple point mutations alter the core peptide sequence

Leader peptides can be swapped between systems

Enables combinatorial biosynthesis approaches

Genome Mining

Bioinformatic identification of RiPP gene clusters

Precursor peptide identification by conserved leader sequences

Discovery of novel classes continues at rapid pace

Engineering Applications

- Phage display-like selection of RiPP variants

Integration with synthetic biology platforms

Drug development: macrocyclic peptidomimetics

References

Post-Translational Modifications (PTMs) in IDPs

PKS-NRPS Hybrid Systems