Mechanism and scope of azetidine-1-carboxylic acid synthases

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Azetidine-1-carboxylic acid (AZE) is a non-canonical ⍺-amino acid found as a building block of several microbial secondary metabolites with interesting properties. It has recently been shown that AZE is derived from S-adenosyl-methionine (SAM) via the action of AZE synthases, enzymes that resemble class-I methyltransferases and that are hence commonly misannotated in sequence databases. The research proposed here aims at unravelling the catalytic mechanism of AZE synthases, using the unpublished crystal structure of an enzyme from Saccharotrix sp. NRRL B-16348 together with SAM derivatives sourced from other groups of the FOR as a springboard for a structure-based biochemical approach. Further, by tapping into the collection of non-natural SAM derivatives that will become available within the FOR, the substrate spectrum of AZE synthases will be analyzed, potentially leading to new congeners for incorporation into AZE-containing natural products. Finally, previously uncharacterized proteins with significant sequence similarity to AZE synthase will be investigated to identify general sequence signatures of AZE synthases and to potentially discover enzymes that catalyze novel SAM-dependent reactions.