Molecular basis for azetidine-2-carboxylic acid biosynthesis
Abstract Azetidine-2-carboxylic acid (AZE) is a long-known plant metabolite. Recently, AZE synthases have been identified in bacterial natural product pathways involving non-ribosomal peptide synthetases. AZE synthases catalyse the intramolecular 4-exo-tet cyclisation of S-adenosylmethionine (SAM),...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56610-6 |
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| author | Tim J. Klaubert Jonas Gellner Charles Bernard Juliana Effert Carine Lombard Ville R. I. Kaila Helge B. Bode Yanyan Li Michael Groll |
| author_facet | Tim J. Klaubert Jonas Gellner Charles Bernard Juliana Effert Carine Lombard Ville R. I. Kaila Helge B. Bode Yanyan Li Michael Groll |
| author_sort | Tim J. Klaubert |
| collection | DOAJ |
| description | Abstract Azetidine-2-carboxylic acid (AZE) is a long-known plant metabolite. Recently, AZE synthases have been identified in bacterial natural product pathways involving non-ribosomal peptide synthetases. AZE synthases catalyse the intramolecular 4-exo-tet cyclisation of S-adenosylmethionine (SAM), yielding a highly strained heterocycle. Here, we combine structural and biochemical analyses with quantum mechanical calculations and mutagenesis studies to reveal catalytic insights into AZE synthases. The cyclisation of SAM is facilitated by an exceptional substrate conformation and supported by desolvation effects as well as cation-π interactions. In addition, we uncover related SAM lyases in diverse bacterial phyla, suggesting a wider prevalence of AZE-containing metabolites than previously expected. To explore the potential of AZE as a proline mimic in combinatorial biosynthesis, we introduce an AZE synthase into the pyrrolizixenamide pathway and thereby engineer analogues of azabicyclenes. Taken together, our findings provide a molecular framework to understand and exploit SAM-dependent cyclisation reactions. |
| format | Article |
| id | doaj-art-3b64b03c564f48c998709093aad73212 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3b64b03c564f48c998709093aad732122025-02-09T12:45:26ZengNature PortfolioNature Communications2041-17232025-02-0116111210.1038/s41467-025-56610-6Molecular basis for azetidine-2-carboxylic acid biosynthesisTim J. Klaubert0Jonas Gellner1Charles Bernard2Juliana Effert3Carine Lombard4Ville R. I. Kaila5Helge B. Bode6Yanyan Li7Michael Groll8Center for Protein Assemblies, Department Bioscience, School of Natural Sciences, Technical University MunichCenter for Protein Assemblies, Department Bioscience, School of Natural Sciences, Technical University MunichLaboratory Molecules of Communication and Adaptation of Microorganisms (MCAM), UMR 7245 CNRS-MNHN (Muséum National d’Histoire Naturelle)Max Planck Institute for Terrestrial Microbiology, Department of Natural Products in Organismic InteractionsLaboratory Molecules of Communication and Adaptation of Microorganisms (MCAM), UMR 7245 CNRS-MNHN (Muséum National d’Histoire Naturelle)Department of Biochemistry and Biophysics, Stockholm UniversityMax Planck Institute for Terrestrial Microbiology, Department of Natural Products in Organismic InteractionsLaboratory Molecules of Communication and Adaptation of Microorganisms (MCAM), UMR 7245 CNRS-MNHN (Muséum National d’Histoire Naturelle)Center for Protein Assemblies, Department Bioscience, School of Natural Sciences, Technical University MunichAbstract Azetidine-2-carboxylic acid (AZE) is a long-known plant metabolite. Recently, AZE synthases have been identified in bacterial natural product pathways involving non-ribosomal peptide synthetases. AZE synthases catalyse the intramolecular 4-exo-tet cyclisation of S-adenosylmethionine (SAM), yielding a highly strained heterocycle. Here, we combine structural and biochemical analyses with quantum mechanical calculations and mutagenesis studies to reveal catalytic insights into AZE synthases. The cyclisation of SAM is facilitated by an exceptional substrate conformation and supported by desolvation effects as well as cation-π interactions. In addition, we uncover related SAM lyases in diverse bacterial phyla, suggesting a wider prevalence of AZE-containing metabolites than previously expected. To explore the potential of AZE as a proline mimic in combinatorial biosynthesis, we introduce an AZE synthase into the pyrrolizixenamide pathway and thereby engineer analogues of azabicyclenes. Taken together, our findings provide a molecular framework to understand and exploit SAM-dependent cyclisation reactions.https://doi.org/10.1038/s41467-025-56610-6 |
| spellingShingle | Tim J. Klaubert Jonas Gellner Charles Bernard Juliana Effert Carine Lombard Ville R. I. Kaila Helge B. Bode Yanyan Li Michael Groll Molecular basis for azetidine-2-carboxylic acid biosynthesis Nature Communications |
| title | Molecular basis for azetidine-2-carboxylic acid biosynthesis |
| title_full | Molecular basis for azetidine-2-carboxylic acid biosynthesis |
| title_fullStr | Molecular basis for azetidine-2-carboxylic acid biosynthesis |
| title_full_unstemmed | Molecular basis for azetidine-2-carboxylic acid biosynthesis |
| title_short | Molecular basis for azetidine-2-carboxylic acid biosynthesis |
| title_sort | molecular basis for azetidine 2 carboxylic acid biosynthesis |
| url | https://doi.org/10.1038/s41467-025-56610-6 |
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