Structure−Activity Relationships of Trichothecene Toxins in an <i>Arabidopsis thaliana</i> Leaf Assay

Desjardins, Anne E.; McCormick, Susan P.; Appell, Michael

doi:10.1021/jf0709193

Cited by 75 publications

(66 citation statements)

References 27 publications

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“…However, the number and position of hydroxyl and acetyl ester groups on the trichothecene structure can also influence the mechanism of protein synthesis inhibition and relative toxicities within eukaryotic cells (32)(33)(34). In this regard, we found that the position of an acetyl ester group on either carbon 3 or 15 of DON (Fig.…”

Section: Discussionmentioning

confidence: 76%

Intracellular Expression of a Single Domain Antibody Reduces Cytotoxicity of 15-Acetyldeoxynivalenol in Yeast

Doyle

Saeed

Hermans

et al. 2009

Journal of Biological Chemistry

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15-Acetyldeoxynivalenol (15-AcDONFusarium head blight of cereals and Fusarium ear rot of maize are caused by morphologically similar species (Fusarium graminearum and Fusarium culmorum, etc.) common throughout global agricultural regions. With few exceptions, Fusarium epidemics are characterized by cyclical and highly aggressive infection of commercial crops with economic impacts on food and feed industries that are immediate and far reaching. For example, losses associated with the most recent Fusarium outbreak in North America in the 1990s were estimated to range from 1.3 to 3.0 billion United States dollars (1).A toxin class commonly found within agricultural commodities infected by Fusarium are trichothecene mycotoxins. Trichothecenes represent a highly diverse group of over 180 sesquiterpenoid low molecular weight (typically 200 -500 Da) mycotoxins characterized by a tricyclic ring structure containing a double bond at C-9,10 and an epoxide group at C-13 (2). Regardless of size and structural composition, trichothecenes are potent inhibitors of eukaryotic protein synthesis with specific activity on ribosomal protein L3 within the 60 S subunit resulting in inhibition of peptidyltransferase activity (3, 4). Although the capacity to inhibit protein synthesis is regarded as central to trichothecene cytotoxicity (5, 6), adverse effects on eukaryotic cells may actually be attributed to dysregulation of cellular signaling and alterations in downstream gene expression (7). As a result, trichothecenes such as deoxynivalenol (DON), 2 15-acetyldeoxynivalenol (15-AcDON), and 3-acetyldeoxynivalenol (3-AcDON) (Fig. 1) are considered to be inherently hazardous feed-and foodborne contaminants (2,8).Numerous studies have demonstrated a correlation between in planta DON accumulation and Fusarium virulence in susceptible cultivars of wheat (9) and maize (10). Based on these findings, mechanisms that convey innate and acquired host plant resistance to DON and other trichothecene toxins have received considerable attention. To date, in planta trichothecene resistance has been achieved through mechanisms that alter targeted proteins within host cell ribosomes (11, 12), promote metabolic transformation to less toxic forms, e.g. DONglucosyl conjugate (13) or to 3-AcDON (14), and/or reduce intracellular concentrations to effectively limit mycotoxin exposure to sensitive cellular targets. Collectively, such research can be applied to impart novel mechanisms of trichothecene resistance in higher order plants.Yeast is well suited as a eukaryotic model organism to identify and validate mechanisms involved in host plant resistance to mycotoxins (12,13,15). Test systems based on yeast offer cost-effective convenience and flexibility as one can validate a wide range of novel detoxification mechanisms within a short period of time at a minimal cost using common/nonspecialized laboratory equipment. Assessment of mycotoxin resistance *

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Section: Discussionmentioning

confidence: 76%

Intracellular Expression of a Single Domain Antibody Reduces Cytotoxicity of 15-Acetyldeoxynivalenol in Yeast

Doyle

Saeed

Hermans

et al. 2009

Journal of Biological Chemistry

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“…Tcin was isolated from Trichothecium roseum and prepared as described (12). DAS, T-2, and DON were prepared as described (41).…”

Section: Methodsmentioning

confidence: 99%

Elimination of damaged mitochondria through mitophagy reduces mitochondrial oxidative stress and increases tolerance to trichothecenes

Bin-Umer

McLaughlin

Butterly

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Trichothecene mycotoxins are natural contaminants of small grain cereals and are encountered in the environment, posing a worldwide threat to human and animal health. Their mechanism of toxicity is poorly understood, and little is known about cellular protection mechanisms against trichothecenes. We previously identified inhibition of mitochondrial protein synthesis as a novel mechanism for trichothecene-induced cell death. To identify cellular functions involved in trichothecene resistance, we screened the Saccharomyces cerevisiae deletion library for increased sensitivity to nonlethal concentrations of trichothecin (Tcin) and identified 121 strains exhibiting higher sensitivity than the parental strain. The largest group of sensitive strains had significantly higher reactive oxygen species (ROS) levels relative to the parental strain. A dose-dependent increase in ROS levels was observed in the parental strain treated with different trichothecenes, but not in a petite version of the parental strain or in the presence of a mitochondrial membrane uncoupler, indicating that mitochondria are the main site of ROS production due to toxin exposure. Cytotoxicity of trichothecenes was alleviated after treatment of the parental strain and highly sensitive mutants with antioxidants, suggesting that oxidative stress contributes to trichothecene sensitivity. Cotreatment with rapamycin and trichothecenes reduced ROS levels and cytotoxicity in the parental strain relative to the trichothecene treatment alone, but not in mitophagy deficient mutants, suggesting that elimination of trichothecene-damaged mitochondria by mitophagy improves cell survival. These results reveal that increased mitophagy is a cellular protection mechanism against trichothecene-induced mitochondrial oxidative stress and a potential target for trichothecene resistance.Fusarium head blight | deoxynivalenol | Fusarium graminearum

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“…Trichoderma arundinaceum and T. brevicompactum also produce trichothecenes, sesquiterpenoid compounds which are harmful to plants and to the animals which consume contaminated food or feed stocks. Several studies on the structure-activity relationships of Fusarium trichothecene toxins in alga, plant, and animal models (5)(6)(7) indicate that certain Fusarium trichothecenes and intermediates have different toxic effects. Using an Arabidopsis leaf assay, Desjardins and coworkers found that toxicity varied Ͼ200-fold between different trichothecene compounds, while trichodiene (TD), a hydrocarbon precursor, was not phytotoxic (6).…”

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confidence: 99%

Effects of Trichothecene Production on the Plant Defense Response and Fungal Physiology: Overexpression of the Trichoderma arundinaceum tri4 Gene in T. harzianum

Cardoza

McCormick

Malmierca

et al. 2015

Appl Environ Microbiol

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dTrichothecenes are fungal sesquiterpenoid compounds, the majority of which have phytotoxic activity. They contaminate food and feed stocks, resulting in potential harm to animals and human beings. Trichoderma brevicompactum and T. arundinaceum produce trichodermin and harzianum A (HA), respectively, two trichothecenes that show different bioactive properties. Both compounds have remarkable antibiotic and cytotoxic activities, but in addition, trichodermin is highly phytotoxic, while HA lacks this activity when analyzed in vivo. Analysis of Fusarium trichothecene intermediates led to the conclusion that most of them, with the exception of the hydrocarbon precursor trichodiene (TD), have a detectable phytotoxic activity which is not directly related to the structural complexity of the intermediate. In the present work, the HA intermediate 12,13-epoxytrichothec-9-ene (EPT) was produced by expression of the T. arundinaceum tri4 gene in a transgenic T. harzianum strain that already produces TD after transformation with the T. arundinaceum tri5 gene. Purified EPT did not show antifungal or phytotoxic activity, while purified HA showed both antifungal and phytotoxic activities. However, the use of the transgenic T. harzianum tri4 strain induced a downregulation of defense-related genes in tomato plants and also downregulated plant genes involved in fungal root colonization. The production of EPT by the transgenic tri4 strain raised levels of erg1 expression and reduced squalene accumulation while not affecting levels of ergosterol. Together, these results indicate the complex interactions among trichothecene intermediates, fungal antagonists, and host plants.A number of Trichoderma species are known for the ability to act as important biocontrol agents against phytopathogenic fungi (1, 2). Trichoderma species are able to act as biofertilizers, to induce plant defense responses, and to increase tolerance to abiotic stresses (3, 4). Trichoderma arundinaceum and T. brevicompactum also produce trichothecenes, sesquiterpenoid compounds which are harmful to plants and to the animals which consume contaminated food or feed stocks. Several studies on the structure-activity relationships of Fusarium trichothecene toxins in alga, plant, and animal models (5-7) indicate that certain Fusarium trichothecenes and intermediates have different toxic effects. Using an Arabidopsis leaf assay, Desjardins and coworkers found that toxicity varied Ͼ200-fold between different trichothecene compounds, while trichodiene (TD), a hydrocarbon precursor, was not phytotoxic (6).Biosynthesis of trichothecenes starts with the cyclization of farnesyl diphosphate (FPP), catalyzed by the terpene cyclase trichodiene synthase encoded by tri5 (8), to produce TD. In Trichoderma, TD is then oxygenated at C-2, C-11, and C-13 by a P450 monooxygenase encoded by tri4 (9, 10) to give the intermediate isotrichodiol, which is nonenzymatically converted to 12,13-epoxytrichothec-9-ene (EPT). The oxygenation of these three carbons is a characteristic that Trichoderma...

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Structure−Activity Relationships of Trichothecene Toxins in an Arabidopsis thaliana Leaf Assay

Cited by 75 publications

References 27 publications

Intracellular Expression of a Single Domain Antibody Reduces Cytotoxicity of 15-Acetyldeoxynivalenol in Yeast

Intracellular Expression of a Single Domain Antibody Reduces Cytotoxicity of 15-Acetyldeoxynivalenol in Yeast

Elimination of damaged mitochondria through mitophagy reduces mitochondrial oxidative stress and increases tolerance to trichothecenes

Effects of Trichothecene Production on the Plant Defense Response and Fungal Physiology: Overexpression of the Trichoderma arundinaceum tri4 Gene in T. harzianum

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