Heterocycles are essential structural motifs of many pharmaceuticals and agrochemicals. As chemical synthesis of heterocycles typically requires harsh reaction conditions and the use of hazardous agents, the synthetic utility of heterocycle-forming enzymes is increasingly investigated. In recent years, several unusual members of the amidohydrolase superfamily were described that catalyze intramolecular condensation reactions to form heterocycles in natural product biosynthesis pathways. The first such enzyme that was characterized in detail was the condensing amidohydrolase MxcM. MxcM was discovered in the biosynthetic pathway of the siderophore pseudochelin A, where it generates an imidazoline moiety via intramolecular condensation of a β-aminoethyl amide group.[1,2,3] In Streptomyces sp. Tü 6176, a homolog of this condensing amidohydrolase produces a benzoxazole during the biosynthesis of nataxazole.[4] A small enzyme cascade consisting of an AMP ligase and the amidohydrolase is sufficient to synthesize benzoxazoles from aryl carboxylic acids. The AMP ligase first catalyzes the dimerization of two building blocks via ester bond formation. Then, the condensing amidohydrolase catalyzes the biosynthesis of the benzoxazole. Heterologous expression of these two enzymes in M. xanthus led to the production of various benzoxazole derivatives in a combinatorial precursor-directed biosynthesis approach.[5] A phylogenetic analysis based on already described condensing amidohydrolases revealed a large variety of homologous enzymes in different bacterial phyla (unpublished data). This finding suggests that other condensing amidohydrolases involved in heterocycle formation exist and that the synthetic potential of this enzyme group has not yet been fully exploited. In this study, a new condensing amidohydrolase originating from a myxobacterium was investigated. Interestingly, our data indicate that the reaction mechanism of this enzyme differs from the one previously described.
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[2] Winand L, Vollmann DJ, Hentschel J, Nett M. Catalysts 2021, 11(8), 892.
[3] Winand L, Theisen S, Lütz S, Rosenthal K, Nett M. Catalysts 2023, 13(2), 229.
[4] Song H, Rao C, Deng Z, Yu Y, Naismith JH. Chem. Int. Ed. Engl. 2020, 59(15), 6054–6061.
[5] Winand L, Lernoud L, Meyners SA, Kuhr K, Hiller W, Nett M. ChemBioChem 2023, 24, e202200635.