Fumonisins and fumonisin analogs as inhibitors of ceramide synthase and inducers of apoptosis

Desai, Kena; Sullards, M. Cameron; Allegood, Jeremy C.; Wang, Elaine; Schmelz, Eva M.; Hartl, Michaela; Humpf, Hans‐Ulrich; Liotta, Dennis; Peng, Qiong; Merrill, Alfred H.

doi:10.1016/s1388-1981(02)00340-2

Cited by 162 publications

(121 citation statements)

References 33 publications

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“…Thus, it appears that a decreased SPT activity, either by mutations or an enzymatic inhibitor of Because an impaired ceramide synthase causes PCD, the death signal(s) are likely the substrates of the enzyme. The currently known substrates of the enzyme include dh-sph and sph [10,12,13], which accumulate to substantially high levels upon treatment with FB 1 or AAL toxin in a variety of plant species [17,21,45] (see also Table 1) as well as several mammalian cell lines [14,52]. The observation that FB 1 causes massively increased sphingoid bases suggests that these compounds are key signal molecules that control plant PCD.…”

Section: Discussionmentioning

confidence: 99%

Involvement of sphingoid bases in mediating reactive oxygen intermediate production and programmed cell death in Arabidopsis

et al. 2007

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Sphingolipids have been suggested to act as second messengers for an array of cellular signaling activities in plant cells, including stress responses and programmed cell death (PCD). However, the mechanisms underpinning these processes are not well understood. Here, we report that an Arabidopsis mutant, fumonisin B1 resistant11-1 (fbr11-1), which fails to generate reactive oxygen intermediates (ROIs), is incapable of initiating PCD when the mutant is challenged by fumonisin B 1 (FB 1 ), a specific inhibitor of ceramide synthase. Molecular analysis indicated that FBR11 encodes a long-chain base1 (LCB1) subunit of serine palmitoyltransferase (SPT), which catalyzes the first rate-limiting step of de novo sphingolipid synthesis. Mass spectrometric analysis of the sphingolipid concentrations revealed that whereas the fbr11-1 mutation did not affect basal levels of sphingoid bases, the mutant showed attenuated formation of sphingoid bases in response to FB 1 . By a direct feeding experiment, we show that the free sphingoid bases dihydrosphingosine, phytosphingosine and sphingosine efficiently induce ROI generation followed by cell death. Conversely, ROI generation and cell death induced by dihydrosphingosine were specifically blocked by its phosphorylated form dihydrosphingosine-1-phosphate in a dosedependent manner, suggesting that the maintenance of homeostasis between a free sphingoid base and its phosphorylated derivative is critical to determining the cell fate. Because alterations of the sphingolipid level occur prior to the ROI production, we propose that the free sphingoid bases are involved in the control of PCD in Arabidopsis, presumably through the regulation of the ROI level upon receiving different developmental or environmental cues.

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Section: Discussionmentioning

confidence: 99%

Involvement of sphingoid bases in mediating reactive oxygen intermediate production and programmed cell death in Arabidopsis

et al. 2007

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“…These data indicate that LASS1 does not utilize cis-C18:1 fatty acid CoAs as substrates in vitro. LASS1 Is a Fumonisin B 1 -sensitive (Dihydro)ceramide Synthase-Fumonisin B 1 is a known inhibitor of (dihydro)ceramide synthase in vitro (26). However, in human embryonic kidney 293T cells overexpressing LASS1, fumonisin B 1 treatment was shown to increase cellular levels of C18 ceramide, suggesting that LASS1 is fumonisin B 1 -insensitive (17).…”

Section: Mutations In the Lag1p Motif Of Lass1 Affect Its Function Inmentioning

confidence: 99%

Necessary Role for the Lag1p Motif in (Dihydro)ceramide Synthase Activity

Spassieva

Seo

Jiang

et al. 2006

Journal of Biological Chemistry

118

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Lag1 (longevity assurance gene 1) homologues, a family of transmembrane proteins found in all eukaryotes, have been shown to be necessary for (dihydro)ceramide synthesis. All Lag1 homologues contain a highly conserved stretch of 52 amino acids known as the Lag1p motif. However, the functional significance of the conserved Lag1p motif for (dihydro)ceramide synthesis is currently unknown. In this work, we have investigated the function of the motif by introducing eight point mutations in the Lag1p motif of the mouse LASS1 (longevity assurance homologue 1 of yeast Lag1). The (dihydro)ceramide synthase activity of the mutants was tested using microsomes in HeLa cells and in vitro. Six of the mutations resulted in loss of activity in cells and in vitro. In addition, our results showed that C18:0 fatty acid CoA (but not cis-C18:1 fatty acid CoAs) are substrates for LASS1 and that LASS1 in HeLa cells is sensitive to fumonisin B 1 , an in vitro inhibitor of (dihydro)-ceramide synthase. Moreover, we mutated the Lag1p motif of another Lag homologue, human LASS5. The amino acid substitutions in the human LASS5 were the same as in mouse LASS1, and had the same effect on the in vitro activity of LASS5, suggesting the Lag1p motif appears to be essential for the enzyme activity of all Lag1 homologues.

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“…Fumonisin B 1 disrupts sphingolipid metabolism by potently inhibiting the enzyme ceramide synthase (sphinganine Nacetyltransferase) in the de noVo biosynthesis pathway of major sphingolipids, thus causing a rapid increase in free sphinganine (Sa), one of the base precursors (11,12). The levels of free Sa and sphingosine (So) in tissues and biological fluids may be compared by constructing a ratio of Sa to So (Sa/So ratio) that is used as an early biomarker of exposure to the mycotoxin (13).…”

Section: Introductionmentioning

confidence: 99%

Glucose Reaction with Fumonisin B₁Partially Reduces Its Toxicity in Swine

Fernandez-Surumay

Osweiler

Yaeger

et al. 2004

J. Agric. Food Chem.

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Acute and subacute intraperitoneal doses of fumonisin B1 (FB1) were administered to test the efficacy of the FB1-glucose reaction products in detoxifying FB1 in swine. In the acute study at 11 µmol of FB1/kg of body weight, five of six pigs administered FB1 and four of six pigs administered FB1-glucose died from acute pulmonary edema. Analysis of weight gain, serum aspartate aminotransferase and γ-glutamyltransferase, total cholesterol, and pathological evaluation did not provide evidence of protection against FB1 toxicity by the FB1-glucose reaction products. In the subacute study at 5.5 µmol of FB1/kg of body weight, one pig administered FB1 died from liver damage. Analysis of serum aspartate aminotransferase, γ-glutamyltransferase, and total bilirubin showed protection against FB1 toxicity by the FB1-glucose reaction products. The levels of sphinganine and sphinganine/sphingosine ratios in serum and liver as well as pathologic findings provided definitive evidence of protection against the FB1 toxic effects by this detoxification procedure (p < 0.05). Acute and subacute intraperitoneal doses of fumonisin B 1 (FB 1 ) were administered to test the efficacy of the FB 1 -glucose reaction products in detoxifying FB 1 in swine. In the acute study at 11 µmol of FB 1 /kg of body weight, five of six pigs administered FB 1 and four of six pigs administered FB 1 -glucose died from acute pulmonary edema. Analysis of weight gain, serum aspartate aminotransferase and γ-glutamyltransferase, total cholesterol, and pathological evaluation did not provide evidence of protection against FB 1 toxicity by the FB 1 -glucose reaction products. In the subacute study at 5.5 µmol of FB 1 /kg of body weight, one pig administered FB 1 died from liver damage. Analysis of serum aspartate aminotransferase, γ-glutamyltransferase, and total bilirubin showed protection against FB 1 toxicity by the FB 1 -glucose reaction products. The levels of sphinganine and sphinganine/sphingosine ratios in serum and liver as well as pathologic findings provided definitive evidence of protection against the FB 1 toxic effects by this detoxification procedure (p < 0.05).

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Fumonisins and fumonisin analogs as inhibitors of ceramide synthase and inducers of apoptosis

Cited by 162 publications

References 33 publications

Involvement of sphingoid bases in mediating reactive oxygen intermediate production and programmed cell death in Arabidopsis

Involvement of sphingoid bases in mediating reactive oxygen intermediate production and programmed cell death in Arabidopsis

Necessary Role for the Lag1p Motif in (Dihydro)ceramide Synthase Activity

Glucose Reaction with Fumonisin B₁Partially Reduces Its Toxicity in Swine

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Fumonisins and fumonisin analogs as inhibitors of ceramide synthase and inducers of apoptosis

Cited by 162 publications

References 33 publications

Involvement of sphingoid bases in mediating reactive oxygen intermediate production and programmed cell death in Arabidopsis

Involvement of sphingoid bases in mediating reactive oxygen intermediate production and programmed cell death in Arabidopsis

Necessary Role for the Lag1p Motif in (Dihydro)ceramide Synthase Activity

Glucose Reaction with Fumonisin B1Partially Reduces Its Toxicity in Swine

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Glucose Reaction with Fumonisin B₁Partially Reduces Its Toxicity in Swine