Recent advances in the biosynthesis of RiPPs from multicore-containing precursor peptides

Abstract

Ribosomally synthesized and post-translationally modified peptides (RiPPs) compose a large structurally and functionally diverse family of natural products. The biosynthesis system of RiPPs typically involves a precursor peptide comprising of a leader and core motif and nearby processing enzymes that recognize the leader and act on the core for producing modified peptides. Interest in RiPPs has increased substantially in recent years as improvements in genome mining techniques have dramatically improved access to these peptides and biochemical and engineering studies have supported their applications. A less understood, intriguing feature in the RiPPs biosynthesis is the precursor peptides of multiple RiPPs families produced by bacteria, fungi and plants carrying multiple core motifs, which we term “multicore”. Herein, we present the prevalence of the multicore systems, their biosynthesis and engineering for applications.

The multifaceted nature of antimicrobial peptides: current synthetic chemistry approaches and future directions

“…They display a wide array of biological activites, such as inhibition of nucleotide/protein synthesis, metal ion chelation, cell membrane permeation, cell apoptosis regulation, cytokine release modulation, or acting as siderophores. 207,[210][211][212][213][214] Although some of these NRPs are key players in the clinic (e.g. vancomycin), there are still very few AMPs that are currently undergoing preclinical studies or clinical trials, approved by the FDA, or undergoing commercial development.…”

Structural Basis for a Dual Function ATP Grasp Ligase That Installs Single and Bicyclic ω-Ester Macrocycles in a New Multicore RiPP Natural Product

“…Genome mining of RiPP BGCs is revealing the presence of precursor peptides that contain multiple core regions in otherwise unrelated RiPP families as observed previously in the cyanobactins 43 and fungal and plant peptides. 44 Recently, Kim and co-workers have greatly expanded the number of examples of multicore graspetides by directing their searches to BGCs containing ATP-grasp ligases and core regions with Ser/Thr nucleophiles and the receiving Asp/Glu amino acids. 21 Biochemical and mass spectrometric characterization of those BGCs revealed new multicore ω-ester-containing peptides with diverse connectivities or topologies.…”

A Silent Biosynthetic Gene Cluster from a Methanotrophic Bacterium Potentiates Discovery of a Substrate Promiscuous Proteusin Cyclodehydratase

“…Here, we posit that RiPP biosynthetic enzymes present in biosynthetic gene clusters (BGCs) containing multiple substrate peptide-encoding genes will inherently be substrate promiscuous as they need to modify different substrates in their native physiological context. This rationalization is supported by the discovery of broadly substrate-tolerant lanthipeptide synthetases that modify numerous different substrate peptides encoded in cyanobacterial genomes. − Also reminiscent are the substrate promiscuous peptide macrocyclases that modify multiple different core regions present in a single substrate peptide for the biosynthesis of cyanobactins, microviridins, and fungal and plant macrocyclic RiPPs . These substrate promiscuous RiPP biosynthetic enzymes can then be used as peptide-modifying biotechnology tools , and also used combinatorically with other RiPP biosynthetic enzymes to build expansive natural product libraries. − …”