Abstract
Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a growing family of natural products that exhibit a range of structures and bioactivities. Initially assembled from the twenty proteinogenic amino acids in a ribosome-dependent manner, RiPPs assume their peculiar bioactive structures through various post-translational modifications. The essential modifications representative of each subfamily of RiPP are performed on a precursor peptide by the so-called processing enzymes; however, various tailoring enzymes can also embellish the precursor peptide or processed peptide with additional functional groups. Lasso peptides are an interesting subfamily of RiPPs characterized by their unique lariat knot-like structure, wherein the C-terminal tail is inserted through a macrolactam ring fused by an isopeptide bond between the N-terminal amino group and an acidic side chain. Until recently, relatively few lasso peptides were found to be tailored with extra functional groups. Nevertheless, the development of new routes to diversify lasso peptides and thus introduce novel or enhanced biological, medicinally relevant, or catalytic properties is appealing. In this review, we highlight several strategies through which lasso peptides have been successfully modified and provide a brief overview of the latest findings on the tailoring of these peptides. We also propose future directions for lasso peptide tailoring as well as potential applications for these peptides in hybrid catalyst design.
Highlights
Peptide natural products are one of the richest sources of biologically active compounds and are derived from numerous natural sources (Dang and Süssmuth, 2017)
Tailoring of Lasso Peptides on their biosynthetic machinery. Members of one such family are synthesized by megadalton, multi-modular enzymatic assembly lines known as nonribosomal peptide synthetases (NRPSs), which produce structurally diverse peptides in a ribosomeindependent manner (Süssmuth and Mainz, 2017)
Compared to peptides assembled by megasynthetases (i.e., NRPSs), the ribosomal origin of ribosomally synthesized and post-translationally modified peptides (RiPPs) allows for significant changes to their chemical structures via sitedirected mutagenesis of precursor peptides (Truman, 2016)
Summary
Peptide natural products are one of the richest sources of biologically active compounds and are derived from numerous natural sources (Dang and Süssmuth, 2017). Microbes produce peptide-derived secondary metabolites that exhibit a wide range of activities (Demain, 1999), including compounds that function in quorum-sensing (e.g., N-acyl homoserine lactones), agents that bind and transport metals (e.g., siderophores like enterobactin), and antibiotics that exert a survival advantage against other microbes (e.g., vancomycin) (Williams et al, 1989). Antibiotic resistance has outpaced the discovery of new antibiotics for years; antimicrobial peptides produced by microorganisms have attracted considerable attention as promising alternatives to the currently limited antibiotic pipeline (Neu, 1992; Newman and Cragg, 2020; Al Musaimi et al, 2021). Peptide natural products can be classified into several families based
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