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

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,...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2016-06, Vol.113 (25), p.6851-6856
Main Authors: Griffiths, Scott, Mesarich, Carl H., Saccomanno, Benedetta, Vaisberg, Abraham, De Wit, Pierre J. G. M., Cox, Russell, Collemare, Jérôme
Format: Article
Language:English
Subjects:
Anthraquinones - chemistry
Anthraquinones - metabolism
Biological activity
Biological Sciences
Biosynthesis
Cladosporium - enzymology
Cladosporium - metabolism
Cytochrome P-450 Enzyme System - metabolism
Cytoxicity
Dimerization
Emodin
Environmental Sciences
Enzymes
Fungi
Gene cluster
Genes
Life Sciences
Metabolites
Nataloe-emodin
Physical Sciences
Secondary metabolism
Vegetal Biology
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Summary: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 β-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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1603528113