The Landscape of Recombination Events That Create Nonribosomal Peptide Diversity
Open accessAbstract
Nonribosomal peptides (NRP) are crucial molecular mediators in microbial ecology and provide indispensable drugs. Nevertheless, the evolution of the flexible biosynthetic machineries that correlates with the stunning structural diversity of NRPs is poorly understood. Here, we show that recombination is a key driver in the evolution of bacterial NRP synthetase (NRPS) genes across distant bacterial phyla, which has guided structural diversification in a plethora of NRP families by extensive mixing and matching of biosynthesis genes. The systematic dissection of a large number of individual recombination events did not only unveil a striking plurality in the nature and origin of the exchange units but allowed the deduction of overarching principles that enable the efficient exchange of adenylation (A) domain substrates while keeping the functionality of the dynamic multienzyme complexes. In the majority of cases, recombination events have targeted variable portions of the Acore domains, yet domain interfaces and the flexible Asub domain remained untapped. Our results strongly contradict the widespread assumption that adenylation and condensation (C) domains coevolve and significantly challenge the attributed role of C domains as stringent selectivity filter during NRP synthesis. Moreover, they teach valuable lessons on the choice of natural exchange units in the evolution of NRPS diversity, which may guide future engineering approaches.
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Amino acid substitutions at R3 most likely occur via recombination events, allowing evolutionary shortcuts.
“However, the amino acid substitutions at R3 most likely occur via recombination events, thereby allowing for evolutionary shortcuts73.”
From Native metabolomics identifies the rivulariapeptolide family of protease inhibitors (2022) · cites this paper as [73]
The Discussion (page unavailable) says recombination can produce substantial amino acid changes and create evolutionary shortcuts. But it does not identify R3 as a site where substitutions most likely occur through recombination; its specific example concerns position 4 of Ahp-cyclodepsipeptides. The Results describe position 3 in that family as highly conserved. (LLM, conf=0.85)
Experimental — accuracy not yet measuredFor Ahp-cyclodepsipeptides, the high structural diversity is mainly driven by hypervariability of amino acids at positions preceding and following the Ahp-unit.
“At least for Ahp-cyclodepsipeptides, recent biosynthetic studies suggest that the high structural diversity of these compounds is mainly driven by the hypervariability of amino acids in the positions proceeding and following the Ahp-unit (see Fig. 4a for the definitions of residues R3 and R2, respectively)73.”
From Native metabolomics identifies the rivulariapeptolide family of protease inhibitors (2022) · cites this paper as [73]
The events impacting R2 can be explained by high-frequency point mutations.
“The events impacting R2 can be explained by high-frequency point mutations.”
From Native metabolomics identifies the rivulariapeptolide family of protease inhibitors (2022) · cites this paper as [73]
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- Authors
- Baunach, M., Chowdhury, S., Stallforth, P., & Dittmann, E.
- Affiliations
- University of Potsdam (DE)
- Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE)
- Corresponding author
- Baunach, Martin
- Venue
- Molecular Biology and Evolution
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-01-22
- Volume
- 38
- Issue
- 5
- Pages
- 2116-2130
- ISSN
- 0737-4038 (ISSN-L)
- 1537-1719
- PMC
- PMC8097286
- OpenAlex
- W3125149014
- Cited by
- 72
- References
- 83
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 15 · 2023: 10 · 2022: 12 · 2021: 10
- FWCI
- 6.85
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Biology and Evolution (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- publish.UP (University of Potsdam) (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (239748522, SFB 1127)
- DFG (RTG 2473)
- Leibniz Association
- Werner Siemens-Stiftung
- Topics
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Keywords
- nonribosomal peptides, genetic recombination, adenylation domain, condensation domain, substrate specificity, multienzyme complex, bacterial secondary metabolites
- MeSH terms
- Multigene Family, Models, Genetic, Peptide Synthases, Recombination, Genetic, Evolution, Molecular, Peptide Biosynthesis, Nucleic Acid-Independent
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