New Class of Ribosomal Peptide with Two Amino Termini

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a large class of natural products synthesized by ribosomes and post-translationally modified. These peptides play important roles in many biological processes, including cell signaling, immune response and antimicrobial defense, and have a wide range of structural and biological activities. Recently, a team of researchers from the University of Illinois at Urbana-Champaign published a research paper entitled "Genome mining unveils a class of ribosomal peptides with two amino termini" in the journal Nature Communications. The team reports a class of RiPPs defined by an unusual (S)-N2,N2-dimethyl-1,2-propanediamine (Dmp)-modified C-terminus, which they named "daptides". Unlike most peptides that have one positively and one negatively charged terminus or "end", daptides have two positively charged termini, so this gives daptides some unique biological activity.

Indeed, finding new RiPPs is not an easy task. Although genome mining has been widely used in various fields, its direct application in RiPP discovery remains challenging, mainly due to the lack of ubiquitous feature across RiPP biosynthetic pathways and the low accuracy of precursor peptide prediction. Class-dependent RiPP genome mining relies on sequence homology with fully characterized biosynthetic enzymes, providing biosynthetic gene clusters (BGC) predictions with high fidelity but potentially reduced chemical structural novelty. Furthermore, key RiPP biosynthetic enzymes, such as cytochrome P450 enzymes or other classes of free radical SAM enzymes, are widely distributed outside of RiPP BGCs. Therefore, the presence of genes encoding such enzymes cannot be used as reliable RiPP biomarkers. An undeveloped approach to identify first-class RiPP is to use the RiPP Recognition Element (RRE), the region responsible for recruiting precursor peptides to RiPP biosynthetic enzymes. By analyzing the RRE, researchers in this project identified nearly 500 daptide BGCs.

Fig. 1 RRE-based discovery of a RiPP class.¹

While this change at the end of daptides may appear small, the positive charge at both ends makes it possible for it to interact with negatively charged objects, such as cell membranes, according to the researchers. To test this, the team added daptides to a culture dish containing red blood cells. They found that the daptides showed hemolytic activity, meaning that they disrupted cell membranes, causing them to rupture, which is relatively rare. The hemolytic activity of these peptides may be used as a new treatment for bacterial infections and cancer. The pathway characterization revealed the biosynthetic pathway of Dmp by direct cloning and reconstitution of synthetic biology methods. Namely, the invariant C-terminal Thr derived from the precursor peptide by sequential oxidative decarboxylation, transamination and dimethylation.

Overall, the discovery of daptides demonstrates genome-independent excavation of the RiPP family of biosynthetic enzymes and provides a logical pathway for the natural production of ribosomal peptides with two amino termini. Future directions for further research include exploring the potential therapeutic use of daptides and the ecological role of daptide production on the bacteria that make them. In addition, many more classes of RiPPs remain to be discovered.

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Reference

1. Ren, Hengqian, et al. "Genome mining unveils a class of ribosomal peptides with two amino termini." Nature Communications 14.1 (2023): 1624.