title: Discovery and reconstitution of the cycloclavine biosynthetic pathway--enzymatic formation of a cyclopropyl group.
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.
authors.affiliation: Department of Biological Chemistry, John Innes Centre, Colney Lane, Norwich (UK).
authors.forename: Dorota
authors.initials: D
authors.lastname: Jakubczyk
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Caputi
authors.forename: Anaëlle
authors.initials: A
authors.lastname: Hatsch
authors.forename: Curt A F
authors.initials: CA
authors.lastname: Nielsen
authors.forename: Melanie
authors.initials: M
authors.lastname: Diefenbacher
authors.forename: Jens
authors.initials: J
authors.lastname: Klein
authors.forename: Andrea
authors.initials: A
authors.lastname: Molt
authors.forename: Hartwig
authors.initials: H
authors.lastname: Schröder
authors.forename: Johnathan Z
authors.initials: JZ
authors.lastname: Cheng
authors.forename: Michael
authors.initials: M
authors.lastname: Naesby
authors.forename: Sarah E
authors.initials: SE
authors.lastname: O'Connor
mesh_terms: D001232:Aspergillus fumigatus / Q000235:genetics; D003521:Cyclopropanes / Q000737:chemistry; D004798:Enzymes / Q000235:genetics / Q000378:metabolism*; D004876:Ergot Alkaloids / Q000096:biosynthesis* / Q000737:chemistry; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D026121:Indole Alkaloids / Q000737:chemistry / Q000378:metabolism*; D005810:Multigene Family; D012441:Saccharomyces cerevisiae / Q000378:metabolism
chemical_list: D003521:Cyclopropanes; D004798:Enzymes; D004876:Ergot Alkaloids; D005656:Fungal Proteins; D026121:Indole Alkaloids; C560517:cycloclavine; C030797:cyclopropane
keywords: biosynthesis; cyclopropyl group; ergot alkaloids; natural products; pathway reconstitution