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Elucidation of cladofulvin biosynthesis reveals a cytochrome P450 monooxygenase required for anthraquinone dimerization

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dc.contributor.author Griffiths, Scott
dc.contributor.author Mesarich, Carl-H.
dc.contributor.author Saccomanno, Benedetta
dc.contributor.author Vaisberg Wollach, Abraham Jaime
dc.contributor.author De-Wit, Pierre-J. G. M.
dc.contributor.author Cox, Russell
dc.contributor.author Collemare, Jerome
dc.date.accessioned 2019-02-06T14:45:34Z
dc.date.available 2019-02-06T14:45:34Z
dc.date.issued 2016
dc.identifier.uri https://hdl.handle.net/20.500.12866/5076
dc.description.abstract Anthraquinones are a large family of secondary metabolites (SMs) that are extensively studied for their diverse biological activities. These activities are determined by functional group decorations and the formation of dimers from anthraquinone monomers. Despite their numerous medicinal qualities, very few anthraquinone biosynthetic pathways have been elucidated so far, including the enzymatic dimerization steps. In this study, we report the elucidation of the biosynthesis of cladofulvin, an asymmetrical homodimer of nataloe-emodin produced by the fungus Cladosporium fulvum A gene cluster of 10 genes controls cladofulvin biosynthesis, which begins with the production of atrochrysone carboxylic acid by the polyketide synthase ClaG and the beta-lactamase ClaF. This compound is decarboxylated by ClaH to yield emodin, which is then converted to chrysophanol hydroquinone by the reductase ClaC and the dehydratase ClaB. We show that the predicted cytochrome P450 ClaM catalyzes the dimerization of nataloe-emodin to cladofulvin. Remarkably, such dimerization dramatically increases nataloe-emodin cytotoxicity against mammalian cell lines. These findings shed light on the enzymatic mechanisms involved in anthraquinone dimerization. Future characterization of the ClaM enzyme should facilitate engineering the biosynthesis of novel, potent, dimeric anthraquinones and structurally related compound families. en_US
dc.language.iso eng
dc.publisher National Academy of Sciences
dc.relation.ispartofseries Proceedings of the National Academy of Sciences of the United States of America
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject cytoxicity en_US
dc.subject emodin en_US
dc.subject gene cluster en_US
dc.subject nataloe-emodin en_US
dc.subject secondary metabolism en_US
dc.subject Anthraquinones/chemistry/metabolism en_US
dc.subject Cladosporium/enzymology/metabolism en_US
dc.subject Cytochrome P-450 Enzyme System/metabolism en_US
dc.subject Dimerization en_US
dc.title Elucidation of cladofulvin biosynthesis reveals a cytochrome P450 monooxygenase required for anthraquinone dimerization en_US
dc.type info:eu-repo/semantics/article
dc.identifier.doi https://doi.org/10.1073/pnas.1603528113
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#1.06.10
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#1.06.01
dc.relation.issn 1091-6490


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