ArticleNature chemical biology2024
Metagenomic domain substitution for the high-throughput modification of nonribosomal peptides.
Article in Nature chemical biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 24 citations in OpenAlex.
- Generative AI designs functional thiolation domains for reprogramming non-ribosomal peptide synthetases.Nature communications · 2026Article
- Mapping the nonribosomal specificity code through promiscuity-guided A-domain engineering.Chemical science · 2026Article
- Advances in natural product discovery: strategies, technologies, and insights.Natural products and bioprospecting · 2026Review
- High-Throughput Engineering and Modification of Non-Ribosomal Peptide Synthetases Based on Golden Gate Assembly.Angewandte Chemie (International ed. in English) · 2025Article
- Synthetic Biology in Natural Product Biosynthesis.Chemical reviews · 2025Review
- Engineering of acyl ligase domain in non-ribosomal peptide synthetases to change fatty acid moieties of lipopeptides.Communications chemistry · 2025Article
- Structure, Function and Engineering of the Nonribosomal Peptide Synthetase Condensation Domain.International journal of molecular sciences · 2024Review
- Synthetic Biology of Natural Products Engineering: Recent Advances Across the Discover-Design-Build-Test-Learn Cycle.ACS synthetic biology · 2024Review
- Functional Diversity and Engineering of the Adenylation Domains in Nonribosomal Peptide Synthetases.Marine drugs · 2024Review
- Biosynthesis of a clickable pyoverdine via in vivo enzyme engineering of an adenylation domain.Microbial cell factories · 2024Article
- Controlling Substrate- and Stereospecificity of Condensation Domains in Nonribosomal Peptide Synthetases.ACS chemical biology · 2024Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 3 countries.
Funding
Abstract
The modular nature of nonribosomal peptide biosynthesis has driven efforts to generate peptide analogs by substituting amino acid-specifying domains within nonribosomal peptide synthetase (NRPS) enzymes. Rational NRPS engineering has increasingly focused on finding evolutionarily favored recombination sites for domain substitution. Here we present an alternative evolution-inspired approach that involves large-scale diversification and screening. By amplifying amino acid-specifying domains en masse from soil metagenomic DNA, we substitute more than 1,000 unique domains into a pyoverdine NRPS. Initial fluorescence and mass spectrometry screens followed by sequencing reveal more than 100 functional domain substitutions, collectively yielding 16 distinct pyoverdines as major products. This metagenomic approach does not require the high success rates demanded by rational NRPS engineering but instead enables the exploration of large numbers of substitutions in parallel. This opens possibilities for the discovery and production of nonribosomal peptides with diverse biological activities.
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Registered trials
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