title: Polyketide decarboxylative chain termination preceded by o-sulfonation in curacin a biosynthesis.
abstract: Biosynthetic innovation in natural product systems is driven by the recruitment of new genes and enzymes into these complex pathways. Here, an unprecedented decarboxylative chain termination mechanism is described for the polyketide synthase of curacin A, an anticancer lead compound isolated from the marine cyanobacterium Lyngbya majuscula. The unusual chain termination module containing adjacent sulfotransferase (ST) and thioesterase (TE) catalytic domains embedded in CurM was biochemically characterized. The TE was proved to catalyze a hydrolytic chain release of the polyketide chain elongation intermediate. Moreover, a selective ST-mediated sulfonation of the (R)-beta-hydroxyl group was found to precede TE-mediated hydrolysis, triggering a successive decarboxylative elimination and resulting in the formation of a rare terminal olefin in the final metabolite.
authors.affiliation: Life Sciences Institute, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Liangcai
authors.initials: L
authors.lastname: Gu
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Amol
authors.initials: A
authors.lastname: Kulkarni
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Gehret
authors.forename: Kayla R
authors.initials: KR
authors.lastname: Lloyd
authors.forename: Lena
authors.initials: L
authors.lastname: Gerwick
authors.forename: William H
authors.initials: WH
authors.lastname: Gerwick
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.forename: Kristina
authors.initials: K
authors.lastname: Håkansson
authors.forename: Janet L
authors.initials: JL
authors.lastname: Smith
authors.forename: David H
authors.initials: DH
authors.lastname: Sherman
mesh_terms: D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D000458:Cyanobacteria; D003521:Cyclopropanes / Q000378:metabolism*; D003653:Decarboxylation; D018942:Macrolides / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D048630:Polyketide Synthases / Q000378:metabolism*; D013450:Sulfones; D015238:Sulfotransferases; D013844:Thiazoles / Q000378:metabolism*; D050257:Tubulin Modulators
chemical_list: D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D003521:Cyclopropanes; D018942:Macrolides; D013450:Sulfones; D013844:Thiazoles; D050257:Tubulin Modulators; C095843:curacin A; D048630:Polyketide Synthases; D015238:Sulfotransferases