Insights into a dual function amide oxidase/macrocyclase from lankacidin biosynthesis

Jonathan Dorival, Fanny Risser, Christophe Jacob, Sabrina Collin, Gerald Dräger, Cédric Paris, Benjamin Chagot, Andreas Kirschning, Arnaud Gruez () and Kira J. Weissman ()
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Jonathan Dorival: CNRS-Université de Lorraine, Biopôle de l’Université de Lorraine
Fanny Risser: CNRS-Université de Lorraine, Biopôle de l’Université de Lorraine
Christophe Jacob: CNRS-Université de Lorraine, Biopôle de l’Université de Lorraine
Sabrina Collin: CNRS-Université de Lorraine, Biopôle de l’Université de Lorraine
Gerald Dräger: Leibniz Universität Hannover
Cédric Paris: Université de Lorraine
Benjamin Chagot: CNRS-Université de Lorraine, Biopôle de l’Université de Lorraine
Andreas Kirschning: Leibniz Universität Hannover
Arnaud Gruez: CNRS-Université de Lorraine, Biopôle de l’Université de Lorraine
Kira J. Weissman: CNRS-Université de Lorraine, Biopôle de l’Université de Lorraine

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract Acquisition of new catalytic activity is a relatively rare evolutionary event. A striking example appears in the pathway to the antibiotic lankacidin, as a monoamine oxidase (MAO) family member, LkcE, catalyzes both an unusual amide oxidation, and a subsequent intramolecular Mannich reaction to form the polyketide macrocycle. We report evidence here for the molecular basis for this dual activity. The reaction sequence involves several essential active site residues and a conformational change likely comprising an interdomain hinge movement. These features, which have not previously been described in the MAO family, both depend on a unique dimerization mode relative to all structurally characterized members. Taken together, these data add weight to the idea that designing new multifunctional enzymes may require changes in both architecture and catalytic machinery. Encouragingly, however, our data also show LkcE to bind alternative substrates, supporting its potential utility as a general cyclization catalyst in synthetic biology.

Date: 2018
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DOI: 10.1038/s41467-018-06323-w

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