Protein synthesis inhibition by 8-oxo-12,13-epoxytrichothecenes

Ehrlich, Kenneth C.; Daigle, Kim W.

doi:10.1016/0304-4165(87)90005-5

Cited by 110 publications

(53 citation statements)

References 25 publications

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“…They share a tricyclic nucleus named trichothecene and usually contain an epoxide at C-12 and C-13, which are essential for toxicity (Desjardins et al 1993). Most trichothecenes also have a C-9,10 double bond, which is important for their toxicity (Ehrlich and Daigle 1987). Their chemical structure varies in both the position and the number of hydroxylations, as well as in the position, number and complexity of esterifications (Desjardins et al 1993).…”

Section: Trichothecenesmentioning

confidence: 99%

Effects of trichothecene mycotoxins on eukaryotic cells: A review

Rocha

Ansari²,

Doohan³

2005

Food Additives and Contaminants

485

298

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The major products of the trichothecene mycotoxin biosynthetic pathway produced in a species-and sometimes isolatespecific manner by cereal-pathogenic Fusarium fungi include T-2 toxin, diacetoxyscirpenol, deoxynivalenol and nivalenol. This paper briefly reviews the major effects of such trichothecenes on the gross morphology, cytology and molecular signalling within eukaryotic cells. The gross toxic effects of select trichothecenes on animals include growth retardation, reduced ovarian function and reproductive disorders, immuno-compromization, feed refusal and vomiting. The phytotoxic effects of deoxynivalenol on plants can be summarized as growth retardation, inhibition of seedling and green plant regeneration. Trichothecenes are now recognized as having multiple inhibitory effects on eukaryote cells, including inhibition of protein, DNA and RNA synthesis, inhibition of mitochondrial function, effects on cell division and membrane effects. In animal cells, they induce apoptosis, a programmed cell death response. Current knowledge about the eukaryotic signal transduction cascades and downstream gene products activated by trichothecenes is limited, especially in plants. In mammalian cells, certain trichothecenes trigger a ribotoxic stress response and activate mitogen-activated protein kinases. DON mediates the inflammatory response by modulating the binding activities of specific transcription factors and subsequently inducing cytokine gene expression. Several genes are up-regulated in wheat in response to trichothecene mycotoxins; the significance, if any, of these genes in the host response to trichothecenes has yet to be elucidated.

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Section: Trichothecenesmentioning

confidence: 99%

Effects of trichothecene mycotoxins on eukaryotic cells: A review

Rocha

Ansari²,

Doohan³

2005

Food Additives and Contaminants

485

298

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“…Trichothecenes such as satratoxin H have been shown to potently inhibit protein synthesis and thymocyte proliferation. 4,5) In addition to immunological toxicity, 6) several reports have suggested a possible relationship between trichothecenes and disorders of central nervous system. Observations include a severe loss of neurons in the cerebral hemisphere and the brain stem, and loss of cerebellar Purkinje cells and dorsal and ventral nervous tissue of the spinal cord.…”

mentioning

confidence: 99%

Satratoxin H Generates Reactive Oxygen Species and Lipid Peroxides in PC12 Cells

Nusuetrong

Pengsuparp

Meksuriyen

et al. 2008

Biological & Pharmaceutical Bulletin

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Satratoxin H, a mycotoxin, is thought to induce apoptosis of PC12 cells through the activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) in a glutathione (GSH)-sensitive manner. The present study was undertaken to further elucidate the mechanism by which satratoxin H induces cell death in PC12 cells. Satratoxin H caused apoptosis of PC12 cells within 24-h, as determined by DNA fragmentation and flow cytometric analysis. Satratoxin H increased reactive oxygen species (ROS) production and lipid peroxidation, as determined by malondialdehyde formation. These effects were attenuated by incubation of cells with GSH, suggesting that satratoxin H-induced increase in apoptosis of serum-deprived PC12 cells may be partially mediated through the generation of ROS.

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“…Considerable variation exists in the oxygenation pattern of individual trichothecenes, but all are characterized by a 9,10 double bond and a 12,13 epoxide group. These compounds are potent inhibitors of protein synthesis in eukaryotes (2) and prevent polypeptide chain initiation or elongation by binding to 60 S ribosomal subunits (3). From pharmacological and toxicological points of view, trichothecenes are an important group of mycotoxins that cause serious problems of food pollution.…”

mentioning

confidence: 99%

Trichothecene 3-O-Acetyltransferase Protects Both the Producing Organism and Transformed Yeast from Related Mycotoxins

Kimura¹,

Kaneko²,

Komiyama³

et al. 1998

Journal of Biological Chemistry

232

206

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Trichothecene mycotoxins such as deoxynivalenol, 4,15-diacetoxyscirpenol, and T-2 toxin, are potent protein synthesis inhibitors for eukaryotic organisms. The 3-O-acetyl derivatives of these toxins were shown to reduce their in vitro activity significantly as assessed by assays using a rabbit reticulocyte translation system. The results suggested that the introduction of an Oacetyl group at the C-3 position in the biosynthetic pathway works as a resistance mechanism for Fusarium species that produce t-type trichothecenes (trichothecenes synthesized via the precursor trichotriol).A gene responsible for the 3-O-acetylation reaction, Tri101, has been successfully cloned from a Fusarium graminearum cDNA library that was designed to be expressed in Schizosaccharomyces pombe. Fission yeast transformants were selected for their ability to grow in the presence of T-2 toxin, and this strategy allowed isolation of 25 resistant clones, all of which contained a cDNA for Tri101. This is the first drug-inactivating Oacetyltransferase gene derived from antibiotic-producing organisms. The open reading frame of Tri101 codes for a polypeptide of 451 amino acid residues, which shows no similarity to any other proteins reported so far. TRI101 from recombinant Escherichia coli catalyzes O-acetylation of the trichothecene ring specifically at the C-3 position in an acetyl-CoA-dependent manner. By using the Tri101 cDNA as a probe, two least overlapping cosmid clones that cover a region of 70 kilobase pairs have been isolated from the genome of F. graminearum. Other trichothecene biosynthetic genes, Tri4, Tri5, and Tri6, were not clustered in the region covered by these cosmid clones. These new cosmid clones are considered to be located in other parts of the large biosynthetic gene cluster and might be useful for the study of trichothecene biosynthesis.Trichothecenes belong to a family of sesquiterpenoid secondary metabolites produced by Fusarium species and other molds (1). Considerable variation exists in the oxygenation pattern of individual trichothecenes, but all are characterized by a 9,10 double bond and a 12,13 epoxide group. These compounds are potent inhibitors of protein synthesis in eukaryotes (2) and prevent polypeptide chain initiation or elongation by binding to 60 S ribosomal subunits (3). From pharmacological and toxicological points of view, trichothecenes are an important group of mycotoxins that cause serious problems of food pollution. They have been implicated in incidents of mycotoxicosis such as vomiting, dermatitis, and hemorrhagic septicemia in humans and livestock (4).The trichothecene biosynthetic pathway has been studied in detail by the use of blocked mutants and by precursor feeding experiments. The proposed pathway in Fusarium species (see Fig. 1) proceeds from mevalonate via farnesyl pyrophosphate, trichodiene (5), isotrichodiol (tricho-9-ene-2␣,11␣-diol) (6), isotrichotriol (tricho-9-ene-2␣,3␣,11␣-triol) (7, 8), trichotriol (tricho-10-ene-2␣,3␣,9␣-triol) (8, 9), isotrichodermol (3␣-hydroxytrichothecene...

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Protein synthesis inhibition by 8-oxo-12,13-epoxytrichothecenes

Cited by 110 publications

References 25 publications

Effects of trichothecene mycotoxins on eukaryotic cells: A review

Effects of trichothecene mycotoxins on eukaryotic cells: A review

Satratoxin H Generates Reactive Oxygen Species and Lipid Peroxides in PC12 Cells

Trichothecene 3-O-Acetyltransferase Protects Both the Producing Organism and Transformed Yeast from Related Mycotoxins

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