New developments in RiPP discovery, enzymology and engineering

Abstract

This review provides a comprehensive update of the advances in discovery, biosynthesis, and engineering of ribosomally-synthesized and post-translationally modified peptides (RiPPs).

Mechanisms and Evolution of Diversity-Generating RiPP Biosynthesis

“…Lanthipeptide bioactivities include antiviral [16], morphogenic [17], antifungal [18], antiallodynic [19], and antimicrobial (called lantibiotics) [20]. Enzymatic modification in lanthipeptides, and most RiPPs, is unusual because changes made to the core peptide sequence are often tolerated by the modifying enzymes provided the leader peptide sequence is kept invariable [8,9]. This separation of substrate recognition in the leader peptide and catalysis on the core peptide has greatly facilitated combinatorial approaches to assess structure-activity relationships [21][22][23][24][25] and bioengineering efforts [26][27][28][29][30][31][32] with lanthipeptides.…”

“…This review focuses specifically on unusual biosynthetic pathways that appear to have evolved to access high molecular diversity for two classes of natural products produced in cyanobacteria, lanthipeptides (see Glossary) and cyanobactins. Both belong to a large group of natural products called ribosomally synthesized and post-translationally modified peptides (RiPPs) [8]. We first provide an overview of their biosynthetic pathways, then discuss the mechanisms of diversity generation, and finish with possible evolutionary implications.…”

Bacteriocins to Thwart Bacterial Resistance in Gram Negative Bacteria

“…The general biosynthetic pathway of microcins (which also applies to other bacteriocins) starts with the ribosomal synthesis of a precursor peptide that is typically composed of two regions, an N-terminal leader part and a core region. The core peptide of modified microcins, which belong to the wide RiPP family, is the region where the PTMs take place (Montalbán-López et al, 2020). In some cases, such as the siderophore microcins, the modifications may result from the non-ribosomal pathway, making these microcins a rare bridge spanning ribosomal and non-ribosomal biosynthesis pathways (McIntosh et al, 2009).…”

“…Their biological characteristics and activities have been deeply described in a new web-accessible database named BACTIBASE, which is freely available at the http://bactibase.pfba-lab.org web-based platform. Bacteriocins can be either unmodified or posttranslationally modified peptides, the latter thus belonging to the large family of ribosomally synthesized and posttranslationally modified peptides (RiPPs) (Arnison et al, 2013;Montalbán-López et al, 2020). Known as inhibitors of pathogens in vitro, many bacteriocins have a high specific activity against clinical strains including antibiotic-resistant ones (Cotter et al, 2013).…”

Diverse Taxonomies for Diverse Chemistries: Enhanced Representation of Natural Product Metabolism in UniProtKB

“…Most classes of natural products ( Figure 1 ), including terpenoids [ 1 ], alkaloids [ 4 ], glycosides [ 5 , 6 ], and polyketides [ 7 ], as well as non-ribosomal peptides (NRPs) [ 8 ], are synthesized by complex enzymatic pathways. The exceptions to this rule are the ribosomally synthesized and post-translationally modified peptides (RiPPs), which are encoded directly by the genome and synthesized via the classical transcription/translation machinery [ 9 ]. The genes coding for these pathways are mainly organized in co-regulated (and generally transcriptionally repressed) biosynthetic gene clusters (BGCs) [ 10 , 11 ], which also encode the necessary transcription factors, transporters [ 12 , 13 ], and proteins that protect against the toxic effects of natural products in their “hosts” [ 14 ].…”