Discovery and Reconstitution of the Cycloclavine Biosynthetic Pathway—Enzymatic Formation of a Cyclopropyl Group |
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Authors: | Dr Dorota Jakubczyk Dr Lorenzo Caputi Anaëlle Hatsch Curt A F Nielsen Melanie Diefenbacher Jens Klein Andrea Molt Hartwig Schröder Dr Johnathan Z Cheng Dr Michael Naesby Prof Sarah E O'Connor |
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Institution: | 1. Department of Biological Chemistry, John Innes Centre, Colney Lane, Norwich (UK);2. Evolva SA, Duggingerstrasse 23, Reinach (Switzerland);3. BASF SE, GVF/D—A030, Ludwigshafen (Germany) |
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Abstract: | The ergot alkaloids, a class of fungal‐derived natural products with important biological activities, are derived from a common intermediate, chanoclavine‐I, which is elaborated into a set of diverse structures. Herein we report the discovery of the biosynthetic pathway of cycloclavine, a complex ergot alkaloid containing a cyclopropyl moiety. We used a yeast‐based expression platform along with in vitro biochemical experiments to identify the enzyme that catalyzes a rearrangement of the chanoclavine‐I intermediate to form a cyclopropyl moiety. The resulting compound, cycloclavine, was produced in yeast at titers of >500 mg L?1, thus demonstrating the feasibility of the heterologous expression of these complex alkaloids. |
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Keywords: | biosynthesis cyclopropyl group ergot alkaloids natural products pathway reconstitution |
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