Abstract
Lasso peptides are a class of ribosomally synthesized and post-translationally modified peptides (RiPPs) with a unique lariat knot-like fold that endows them with extraordinary stability and biologically relevant activity. However, the biosynthetic mechanism of these fascinating molecules remains largely speculative. Generally, two enzymes (B for processing and C for cyclization) are required to assemble the unusual knot-like structure. Several subsets of lasso peptide gene clusters feature a “split” B protein on separate open reading frames (B1 and B2), suggesting distinct functions for the B protein in lasso peptide biosynthesis. Herein, we provide new insights into the role of the RiPP recognition element (RRE) PadeB1, characterizing its capacity to bind the paeninodin leader peptide and deliver its peptide substrate to PadeB2 for processing.
Highlights
Natural products from microorganisms represent a rich source of new chemical scaffolds
To test whether a B protein could function as two fragments as in the native paeninodin system, the intact B protein of the rubrivinodin system was split by introducing a stop codon, followed by a ribosomal binding site and start codon, between the domain boundaries defined by alignments with native B1 and B2 proteins[19]
We demonstrated the reversibility of B protein splitting and fusion, revealing that both routes are feasible from an evolutionary standpoint and that the B protein activities could be assigned to distinct domains
Summary
Natural products from microorganisms represent a rich source of new chemical scaffolds. The proteobacterial peptide microcin J25 is synthesized by a pathway involving four gene products: mcjA encodes the precursor peptide; mcjB, an ATP-dependent cysteine protease; mcjC, an ATP-dependent asparagine synthetase homolog; and mcjD, an ABC transporter[25,26,27,28,29,30,31,32] Another recently identified series of proteobacterial lasso peptides, including astexin-1, sphingopyxin I, and caulosegnin I, are synthesized from gene clusters that feature a lasso peptide-specific isopeptidase instead of an ABC transporter[12,15,18,19,33,34,35,36,37]. Further analysis of StmE was not pursued, and no B2 fragment has been characterized
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