Fusaric acid induces a notochord malformation in zebrafish via copper chelation

Abstract

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 × 10(5) M(-1). These results shed light on the toxicity of fusaric acid and the potential teratogenic effects of consuming plants infected with Fusarium sp.

Fusaric acid contributes to virulence of Fusarium oxysporum on plant and mammalian hosts

“…FA was discovered almost 80 years ago (Yabuta et al, 1937) and was the first fungal toxin whose production was detected in planta (G€ aumann, 1957). Its strong phytotoxicity (Niehaus et al, 2014;Stipanovic et al, 2011), moderate toxicity in animals (Porter et al, 1995;Yin et al, 2015) and bacteria (Bacon et al, 2006;Ruiz et al, 2015), and its pharmacological properties (Song and Yee, 2001;Wang and Ng, 1999), make the study of FA biosynthesis and regulation of great interest. Moreover, FA inhibits the growth of fungi, including its producer Fusarium.…”

“…The ability of FA to chelate metal ions, such as iron or copper, has been known for a long time (Lakshminarayanan and Subramanian, 1955;Malini, 1966;Pan et al, 2010;Tamari and Kaji, 1952). In a recent study, FA has been shown to chelate different metal ions, including Fe 21 , Fe 31 , Cu 21 , Mn 21 and Zn 21 (Ruiz et al, 2015;Yin et al, 2015). We thus asked whether the production of FA is required for the growth of F. oxysporum under metallimiting conditions.…”

“…Fusaric acid (FA), a picolinic acid derivative originally isolated from Fusarium heterosporium (Yabuta et al, 1937), was the first fungal phytotoxin isolated from infected host plants (G€ aumann, 1957) and is known for its high phytotoxicity (Niehaus et al, 2014;Stipanovic et al, 2011). FA also exhibits toxicity towards animals, including notochord malformation in zebrafish (Yin et al, 2015), and neurotoxicity in mammals (Porter et al, 1995), and towards bacteria (Bacon et al, 2006;Ruiz et al, 2015). Although several studies on the mode of action of FA have been conducted, the cellular basis of its toxicity remains poorly understood.…”

Fusaric Acid immunotoxicity and MAPK activation in normal peripheral blood mononuclear cells and Thp-1 cells

“…Elevated levels of serotonin results from its impaired regulation and consequently amplifies behaviors distinctive of the firing of serotonergic neurons such as loss of appetite and lethargy 32 . In zebrafish, FA induced teratogenic effects by inhibition of lysyl oxidase (a copper-dependent enzyme) 33 . FA also decreased norepinephrine levels in the brain, heart, spleen and adrenal gland of rats 34 .…”

Fusaric Acid Induces DNA Damage and Post‐Translational Modifications of p53 in Human Hepatocellular Carcinoma (HepG2) Cells

“…It has anti-hypertensive activity in cats, dogs, rabbits, and rats by inhibiting the copper-dependent enzyme dopamine b-hydroxylase, a key enzyme in the synthesis of the neurotransmitter norepinephrine [Hidaka et al, 1969;Terasawa and Kameyama, 1971]. Fusaric acid was also shown to be toxic to zebrafish by chelating copper and inhibiting the enzyme lysyl oxidase resulting in notochord malformation [Yin et al, 2015]. Fusaric acid was also shown to be toxic to zebrafish by chelating copper and inhibiting the enzyme lysyl oxidase resulting in notochord malformation [Yin et al, 2015].…”