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Molecular basis for azetidine-2-carboxylic acid biosynthesis
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Molecular basis for azetidine-2-carboxylic acid biosynthesis
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Journal Article
Molecular basis for azetidine-2-carboxylic acid biosynthesis
2025
Overview
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.
Azetidine-2-carboxylic acid synthases catalyse the formation of the proline analogue azetidine-2-carboxylic acid (AZE) in bacteria. In this work, the authors combine structural and biochemical analyses with quantum mechanical calculations and mutagenesis studies to obtain catalytic insights into AZE synthases.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Acids
/ Azetidinecarboxylic Acid - chemistry
/ Azetidinecarboxylic Acid - metabolism
/ Bacteria
/ Bacterial Proteins - chemistry
/ Bacterial Proteins - genetics
/ Bacterial Proteins - metabolism
/ Biochemistry, Molecular Biology
/ Humanities and Social Sciences
/ Peptide Synthases - chemistry
/ Peptide Synthases - genetics
/ Peptide Synthases - metabolism
/ Proline
/ S-Adenosylmethionine - chemistry
/ S-Adenosylmethionine - metabolism
/ Science
