Culture-independent metagenomic approaches have proven to be effective tools for identifying previously hidden biosynthetic gene clusters (BGCs) encoding novel natural products with potential medical relevance. However, producing these compounds remains challenging as metagenomic BGCs often originate from organisms phylogenetically distant from available heterologous hosts. Lasso peptides, a subclass of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products, exhibit diverse bioactivities, yet no lasso peptide has previously been discovered directly from a metagenome. Here, we report the discovery and heterologous expression of the first soil metagenome-derived lasso peptide. Expression of its biosynthetic gene cluster in Escherichia coli, followed by mass spectrometry analysis, strongly supported the predicted amino acid sequence and lasso structure of the peptide. Notably, this lasso peptide is the first to feature asparagine as the ring-forming residue at position one. Taxonomic analysis of the corresponding BGC identified an uncultivated member of the Steroidobacterales family (Gammaproteobacteria) as the closest known relative of the potential native host. These findings underscore the potential of metagenomic genome mining to reveal structurally novel RiPPs and to expand our understanding of the natural diversity of lasso peptides.

Polyunsaturated fatty acid (PUFA) synthase-like enzymes are best known for their role in membrane lipid biosynthesis in marine bacteria, but have also been repurposed for the assembly of specialized l...

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Phylogenetic analysis is widely used to predict enzyme function, yet building annotated and reusable trees is labor-intensive and requires extensive knowledge about the specific enzymes. Existing reso...

Nature Communications - Rhizosphere microbiomes are shaped by root exudation of diverse organic compounds. Here, the rhizoSMASH algorithm is introduced, which maps microbial genes involved in their...

In microbial ecosystems, metabolic interactions are key determinants of species’ relative abundance and activity. Given the immense number of possible interactions in microbial communities, their expe...

Microbial metabolic gene clusters encode the biosynthesis or catabolism of metabolites that facilitate ecological specialization, mediate microbiome interactions and constitute a major source of medic...

Microbial metabolic gene clusters encode the biosynthesis or catabolism of metabolites that facilitate ecological specialization, mediate microbiome interactions and constitute a major source of medic...

Abstract. Insects are associated with a wide variety of diverse RNA viruses, including iflaviruses, a group of positive stranded RNA viruses that mainly in

The Ziemert lab is interested in the evolution and distribution of bacterial secondary metabolites. These bioactive compounds are especially important in human medicine as the chemical scaffolds are t...