Fusaric acid induces a notochord malformation in zebrafish via copper chelation
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Over a thousand extracts were tested for phenotypic effects in developing zebrafish embryos to identify bioactive molecules produced by endophytic fungi. One extract isolated from Fusarium sp., a widely distributed fungal genus found in soil and often associated with plants, induced an undulated notochord in developing zebrafish embryos. The active compound was isolated and identified as fusaric acid. Previous literature has shown this phenotype to be associated with copper chelation from the active site of lysyl oxidase, but the ability of fusaric acid to bind copper ions has not been well described. Isothermal titration calorimetry revealed that fusaric acid is a modest copper chelator with a binding constant of 4.4 × 105 M−1. These results shed light on the toxicity of fusaric acid and the potential teratogenic effects of consuming plants infected with Fusarium sp.
KeywordsCopper chelation Endophytic fungi Fusaric acid Natural products Zebrafish notochord
This project was supported by an HHMI Professor’s Grant and NSF grant OISE 853408 to S.A.S. We would like to thank Patrick McMillen for recording images of zebrafish embryos, Michael Takase for crystal structure elucidation, Sunil Kumar for ITC guidance and the Endophyte Collection Quito Catolica (CEQCA) for cataloguing the microorganisms that produced the extracts tested here. Endophytes were isolated from plants collected with permission of the Ministerio del Ambiente of Ecuador.
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