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New developments in RiPP discovery, enzymology and engineering.

ABSTRACT: Covering: up to June 2020Ribosomally-synthesized and post-translationally modified peptides (RiPPs) are a large group of natural products. A community-driven review in 2013 described the emerging commonalities in the biosynthesis of RiPPs and the opportunities they offered for bioengineering and genome mining. Since then, the field has seen tremendous advances in understanding of the mechanisms by which nature assembles these compounds, in engineering their biosynthetic machinery for a wide range of applications, and in the discovery of entirely new RiPP families using bioinformatic tools developed specifically for this compound class. The First International Conference on RiPPs was held in 2019, and the meeting participants assembled the current review describing new developments since 2013. The review discusses the new classes of RiPPs that have been discovered, the advances in our understanding of the installation of both primary and secondary post-translational modifications, and the mechanisms by which the enzymes recognize the leader peptides in their substrates. In addition, genome mining tools used for RiPP discovery are discussed as well as various strategies for RiPP engineering. An outlook section presents directions for future research.

SUBMITTER: Montalban-Lopez M

PROVIDER: S-EPMC7864896 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Many ribosomally synthesized and posttranslationally modified peptide classes (RiPPs) are reliant on a domain called the RiPP recognition element (RRE). The RRE binds specifically to a precursor peptide and directs the posttranslational modification enzymes to their substrates. Given its prevalence across various types of RiPP biosynthetic gene clusters (BGCs), the RRE could theoretically be used as a bioinformatic handle to identify novel classes of RiPPs. In addition, due to the high affinity and specificity of most RRE-precursor peptide complexes, a thorough understanding of the RRE domain could be exploited for biotechnological applications. However, sequence divergence of RREs across RiPP classes has precluded automated identification based solely on sequence similarity. Here, we introduce RRE-Finder, a new tool for identifying RRE domains with high sensitivity. RRE-Finder can be used in precision mode to confidently identify RREs in a class-specific manner or in exploratory mode to assist in the discovery of novel RiPP classes. RRE-Finder operating in precision mode on the UniProtKB protein database retrieved ∼25,000 high-confidence RREs spanning all characterized RRE-dependent RiPP classes, as well as several yet-uncharacterized RiPP classes that require future experimental confirmation. Finally, RRE-Finder was used in precision mode to explore a possible evolutionary origin of the RRE domain. The results suggest RREs originated from a co-opted DNA-binding transcriptional regulator domain. Altogether, RRE-Finder provides a powerful new method to probe RiPP biosynthetic diversity and delivers a rich data set of RRE sequences that will provide a foundation for deeper biochemical studies into this intriguing and versatile protein domain.IMPORTANCE Bioinformatics-powered discovery of novel ribosomal natural products (RiPPs) has historically been hindered by the lack of a common genetic feature across RiPP classes. Herein, we introduce RRE-Finder, a method for identifying RRE domains, which are present in a majority of prokaryotic RiPP biosynthetic gene clusters (BGCs). RRE-Finder identifies RRE domains 3,000 times faster than current methods, which rely on time-consuming secondary structure prediction. Depending on user goals, RRE-Finder can operate in precision mode to accurately identify RREs present in known RiPP classes or in exploratory mode to assist with novel RiPP discovery. Employing RRE-Finder on the UniProtKB database revealed several high-confidence RREs in novel RiPP-like clusters, suggesting that many new RiPP classes remain to be discovered.

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New developments in RiPP discovery, enzymology and engineering.

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