Elucidation of cladofulvin biosynthesis reveals a cytochrome P450 monooxygenase required for anthraquinone dimerization
| Autor: | Jérôme Collemare, Abraham Vaisberg, Scott A. Griffiths, Russell J. Cox, Pierre J. G. M. de Wit, Carl H. Mesarich, Benedetta Saccomanno |
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| Přispěvatelé: | Laboratory of Phytopathology, Wageningen University and Research [Wageningen] (WUR), Massey University, Universidad Peruana Cayetano Heredia (UPCH), University of Bristol [Bristol], Leibniz University Hannover, Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Royal Netherlands Academy of Sciences, Jerrold Meinwald, De Wit, Pierre J. G. M., Cox, Russell, Collemare, Jérôme |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Emodin
Cytochrome P-450 Enzyme System/metabolism Stereochemistry cytoxicity [SDV]Life Sciences [q-bio] Anthraquinones Reductase 010402 general chemistry 01 natural sciences Anthraquinone gene cluster emodin chemistry.chemical_compound secondary metabolism nataloe-emodin Cytoxicity Biosynthesis Cytochrome P-450 Enzyme System Polyketide synthase [SDV.BV]Life Sciences [q-bio]/Vegetal Biology Gene cluster Cladosporium/enzymology/metabolism purl.org/pe-repo/ocde/ford#1.06.01 [https] Nataloe-emodin Multidisciplinary biology 010405 organic chemistry Anthraquinones/chemistry/metabolism Cytochrome P450 Monooxygenase 0104 chemical sciences Laboratorium voor Phytopathologie chemistry Biochemistry Dehydratase [SDE]Environmental Sciences Physical Sciences Laboratory of Phytopathology biology.protein Secondary metabolism Cladosporium Dimerization purl.org/pe-repo/ocde/ford#1.06.10 [https] |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America 113 (2016) 25 Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2016, 113 (25), pp.6851-6856. ⟨10.1073/pnas.1603528113⟩ Proceedings of the National Academy of Sciences of the United States of America, 113(25), 6851-6856 Proceedings of the National Academy of Sciences of the United States of America 25 (113), 6851-6856. (2016) |
| ISSN: | 0027-8424 1091-6490 |
| DOI: | 10.1073/pnas.1603528113⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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