scholarly journals Ceramide synthase inhibition by fumonisins: a perfect storm of perturbed sphingolipid metabolism, signaling, and disease

2019 ◽  
Vol 60 (7) ◽  
pp. 1183-1189 ◽  
Author(s):  
Ronald T. Riley ◽  
Alfred H. Merrill
Keyword(s):  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Perfect Storm

scholarly journals Resveratrol Targets Sphingolipid Metabolism to Induce Growth Inhibition in FLT3 ITD Acute Myeloid Leukemia

Proceedings ◽  
2019 ◽  
Vol 40 (1) ◽  
pp. 4
Author(s):  
Ersöz ◽  
Adan
Keyword(s):  
Growth Inhibition ◽  
Cell Fate ◽  
De Novo ◽  
Therapeutic Potential ◽  
Annexin V ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Cytotoxic Effects ◽  
Sphingosine 1 Phosphate ◽  
First Time

Sphingolipids are important signaling lipids which play crucial roles to determine the cell fate. Ceramide, apoptotic central molecule of sphingolipid metabolism, which is produced through de novo pathway by serine palmitoyl transferase (SPT) and can be converted to antiapoptotic sphingosine-1-phosphate (S1P) and glucosyl ceramide (GC) by sphingosine kinase (SK) and glucosyl ceramide synthase (GCS), respectively. It is aimed to investigate therapeutic potential of resveratrol on FLT3-ITD (Internal Tandem Duplication) AML cells and to identify potential mechanism behind resveratrol-mediated growth inhibition by targeting of ceramide metabolism. The cytotoxic effects of resveratrol, SPT inhibitor (myricoin), SK-1 inhibitor (SKI II), GCS inhibitor (PDMP), resveratrol: SPT inhibitor, resveratrol: SK-1 inhibitor and resveratrol: GCS inhibitor combinations on MOLM-13 and MV4-11 FLT3 ITD AML cells were investigated by cell proliferation assay. Apoptosis was evaluated by annexin V/PI double staining. There were synergistic cytotoxic effects of resveratrol with co-administration of SPT inhibitor, SK-1 inhibitor and GCS inhibitor and apoptosis was synergistically induced for resveratrol and its combinations. This preliminary data showed for the first time that resveratrol might inhibit the growth of FLT3 ITD AML cells through targeting ceramide metabolism.

scholarly journals Sphingolipids are involved in Pieris brassicae egg-induced cell death in Arabidopsis thaliana

2021 ◽  
Author(s):  
Raphaël Groux ◽  
Laetitia Fouillen ◽  
Sébastien Mongrand ◽  
Philippe Reymond
Keyword(s):  
Cell Death ◽  
Pieris Brassicae ◽  
Fatty Acyl ◽  
Sphingolipid Metabolism ◽  
Central Component ◽  
Oxygen Species ◽  
Ceramide Synthase ◽  
Large White ◽  
Egg Extract ◽  
Acyl Chains

In Brassicaceae, hypersensitive-like (HR-like) cell death is a central component of direct defenses triggered against eggs of the large white butterfly Pieris brassicae. The signaling pathway leading to HR-like in Arabidopsis is mainly dependent on salicylic acid (SA) accumulation, but downstream components are unclear. Here, we found that treatment with P. brassicae egg extract (EE) trigger changes in expression of sphingolipid metabolism genes in Arabidopsis and Brassica nigra. Disruption of ceramide synthase activity led to a significant decrease of EE-induced HR-like whereas SA signaling and reactive oxygen species levels were unchanged, suggesting that ceramides are downstream activators of HR-like. Sphingolipid quantifications showed that ceramides with C16-0 side-chains accumulated in both species, and this response was independent on SA accumulation. Finally, we provide genetic evidence that the modification of fatty acyl chains of sphingolipids modulates HR-like. Altogether, these results show that sphingolipids play a key and specific role during insect egg-triggered HR-like.

Synthesis and Characterization of Fluorescent Probes for the Development of a Ceramide Synthase FRET-Based Assay

2020 ◽  
Author(s):  
Eduardo Izquierdo ◽  
Mireia Casasampere ◽  
Gemma Fabriàs ◽  
José Luis Abad ◽  
Josefina Casas ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Second Messengers ◽  
Sphingolipid Metabolism ◽  
Synthesis And Characterization ◽  
Ceramide Synthase ◽  
Structural Components ◽  
Fluorescent Properties ◽  
Ceramide Synthases ◽  
In Cells

Ceramides are recognized to occupy a pivotal position in sphingolipid metabolism, playing a fundamental role as membrane structural components, as well as second messengers. Ceramide synthases (CerS) are a family of enzymes that catalyze the N-acylation of sphingosine and dihydrosphingosine, thus controlling the levels of intracellular ceramides. In this work, we present the synthesis and the fluorescent properties of new probes for the development of a FRET-based assay for CerS activity. Based on our previous discovery of spisulosine as a suitable probe for CerS activity in cells, the use of a modified NBD-spisulosine with a clickable fatty acid as CerS substrates may allow the ultimate formation of a bichromophoric reporter for a FRET-based analysis of CerS activity in cells.

scholarly journals Inactivation of Ceramide Synthase 6 in Mice Results in an Altered Sphingolipid Metabolism and Behavioral Abnormalities

2013 ◽  
Vol 288 (29) ◽  
pp. 21433-21447 ◽  
Author(s):  
Philipp Ebel ◽  
Katharina vom Dorp ◽  
Elisabeth Petrasch-Parwez ◽  
Armin Zlomuzica ◽  
Kiyoka Kinugawa ◽  
...  
Keyword(s):  
Expression Patterns ◽  
Acyl Chain ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Acyl Chain Length ◽  
Hind Limbs ◽  
Behavioral Abnormalities ◽  
Ceramide Content ◽  
Ceramide Synthases ◽  
The Brain

The N-acyl chain length of ceramides is determined by the specificity of different ceramide synthases (CerS). The CerS family in mammals consists of six members with different substrate specificities and expression patterns. We have generated and characterized a mouse line harboring an enzymatically inactive ceramide synthase 6 (CerS6KO) gene and lacz reporter cDNA coding for β-galactosidase directed by the CerS6 promoter. These mice display a decrease in C16:0 containing sphingolipids. Relative to wild type tissues the amount of C16:0 containing sphingomyelin in kidney is ∼35%, whereas we find a reduction of C16:0 ceramide content in the small intestine to about 25%. The CerS6KO mice show behavioral abnormalities including a clasping abnormality of their hind limbs and a habituation deficit. LacZ reporter expression in the brain reveals CerS6 expression in hippocampus, cortex, and the Purkinje cell layer of the cerebellum. Using newly developed antibodies that specifically recognize the CerS6 protein we show that the endogenous CerS6 protein is N-glycosylated and expressed in several tissues of mice, mainly kidney, small and large intestine, and brain.

Fumonisin elimination and prospects for detoxification by enzymatic transformation

2011 ◽  
Vol 4 (3) ◽  
pp. 271-283 ◽  
Author(s):  
D. Hartinger ◽  
W. Moll
Keyword(s):  
Fusarium Verticillioides ◽  
Sphingolipid Metabolism ◽  
Special Focus ◽  
Ceramide Synthase ◽  
Enzymatic Transformation ◽  
Exophiala Spinifera ◽  
Food And Feed ◽  
Feed Enzymes ◽  
Enzymatic Mechanisms ◽  
Enzymatic Detoxification

A technology to efficiently reduce the concentration of carcinogenic and toxic fumonisins in food and feed would be desirable. This class of mycotoxins is produced by the maize pathogen Fusarium verticillioides and other fungi. Fumonisins are frequently found in maize from the warm growing regions of the world, sometimes in considerable concentrations. Their molecular similarity with sphingolipids enables their binding to mammalian ceramide synthase, and the resulting interference with sphingolipid metabolism. Recently, we reported on a cluster of genes of Sphingopyxis sp. MTA144 which enables this alphaproteobacterium to degrade fumonisins. These and the previously known fumonisin catabolism genes and enzymes from the black yeast Exophiala spinifera and from bacterium ATCC 55552 allow the consideration of prospects for enzymatic detoxification of fumonisins in food and feed. All the known fumonisin catabolism pathways start by hydrolytic release of the two tricarballylic acid side chains, followed by removal of the 2-amino group from the core chain by different enzymatic mechanisms. The potential for application of feed enzymes for fumonisin detoxification in the gastrointestinal tract of animals is discussed, and possible applications in processing of maize for feed or food are also considered. To be able to evaluate the requirement for, and potential of, a new, enzyme-based fumonisin detoxification technology, an overview of the state of the art of fumonisin elimination and the known chemical reactions of fumonisins in processing or decontamination is also given. There is a special focus on the toxicity of hydrolysed fumonisins, because they can be generated from fumonisins both by an established, traditional method of maize processing, nixtamalisation, and by enzymatic biotransformation. As a complement to other approaches, enzymatic degradation of fumonisins to ameliorate the health risk of contaminated maize for animals, and possibly also for humans, seems feasible.

scholarly journals Ceramide Synthesis Is Modulated by the Sphingosine Analog FTY720 via a Mixture of Uncompetitive and Noncompetitive Inhibition in an Acyl-CoA Chain Length-de pend ent Manner

2009 ◽  
Vol 284 (24) ◽  
pp. 16090-16098 ◽  
Author(s):  
Sujoy Lahiri ◽  
Hyejung Park ◽  
Elad L. Laviad ◽  
Xuequan Lu ◽  
Robert Bittman ◽  
...  
Keyword(s):  
Chain Length ◽  
Cultured Cells ◽  
De Novo ◽  
Biological Effects ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Noncompetitive Inhibition ◽  
Ceramide Synthesis ◽  
Ceramide Synthases

FTY720, a sphingosine analog, is in clinical trials as an immunomodulator. The biological effects of FTY720 are believed to occur after its metabolism to FTY720 phosphate. However, very little is known about whether FTY720 can interact with and modulate the activity of other enzymes of sphingolipid metabolism. We examined the ability of FTY720 to modulate de novo ceramide synthesis. In mammals, ceramide is synthesized by a family of six ceramide synthases, each of which utilizes a restricted subset of acyl-CoAs. We show that FTY720 inhibits ceramide synthase activity in vitro by noncompetitive inhibition toward acyl-CoA and uncompetitive inhibition toward sphinganine; surprisingly, the efficacy of inhibition depends on the acyl-CoA chain length. In cultured cells, FTY720 has a more complex effect, with ceramide synthesis inhibited at high (500 nm to 5 μm) but not low (<200 nm) sphinganine concentrations, consistent with FTY720 acting as an uncompetitive inhibitor toward sphinganine. Finally, electrospray ionization-tandem mass spectrometry demonstrated, unexpectedly, elevated levels of ceramide, sphingomyelin, and hexosylceramides after incubation with FTY720. Our data suggest a novel mechanism by which FTY720 might mediate some of its biological effects, which may be of mechanistic significance for understanding its mode of action.

scholarly journals Sphingosine-1-Phosphate Phosphohydrolase Regulates Endoplasmic Reticulum-to-Golgi Trafficking of Ceramide

2006 ◽  
Vol 26 (13) ◽  
pp. 5055-5069 ◽  
Author(s):  
Paola Giussani ◽  
Michael Maceyka ◽  
Hervé Le Stunff ◽  
Aki Mikami ◽  
Sandrine Lépine ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Trafficking ◽  
Fluorescent Protein ◽  
Fumonisin B1 ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
C Protein ◽  
Sphingosine 1 Phosphate ◽  
Green Fluorescent ◽  
Ceramide Accumulation

ABSTRACT Previous studies demonstrated that sphingosine-1-phosphate (S1P) phosphohydrolase 1 (SPP-1), which is located mainly in the endoplasmic reticulum (ER), regulates sphingolipid metabolism and apoptosis (H. Le Stunff et al., J. Cell Biol. 158:1039-1049, 2002). We show here that the treatment of SPP-1-overexpressing cells with S1P, but not with dihydro-S1P, increased all ceramide species, particularly the long-chain ceramides. This was not due to inhibition of ceramide metabolism to sphingomyelin or monohexosylceramides but rather to the inhibition of ER-to-Golgi trafficking, determined with the fluorescent ceramide analog N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)-d-erythro-sphingosine (DMB-Cer). Fumonisin B1, an inhibitor of ceramide synthase, prevented S1P-induced elevation of all ceramide species and corrected the defect in ER transport of DMB-Cer, readily allowing its detection in the Golgi. In contrast, ceramide accumulation had no effect on either the trafficking or the metabolism of 6-([N-(7-nitrobenzo-2-oxa-1,3-diazol-4-yl)amino]hexanoyl)-sphingosine, which rapidly labels the Golgi even at 4°C. Protein trafficking from the ER to the Golgi, determined with vesicular stomatitis virus ts045 G protein fused to green fluorescent protein, was also inhibited in SPP-1-overexpressing cells in the presence of S1P but not in the presence of dihydro-S1P. Our results suggest that SPP-1 regulates ceramide levels in the ER and thus influences the anterograde membrane transport of both ceramide and proteins from the ER to the Golgi apparatus.

scholarly journals Sphingosine-1-phosphate phosphohydrolase in regulation of sphingolipid metabolism and apoptosis

2002 ◽  
Vol 158 (6) ◽  
pp. 1039-1049 ◽  
Author(s):  
Hervé Le Stunff ◽  
Ismael Galve-Roperh ◽  
Courtney Peterson ◽  
Sheldon Milstien ◽  
Sarah Spiegel
Keyword(s):  
Cell Fate ◽  
De Novo ◽  
Fumonisin B1 ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Serine Palmitoyltransferase ◽  
Intracellular Membranes ◽  
Sphingosine 1 Phosphate ◽  
Ceramide Accumulation ◽  
Membrane Treatment

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates diverse biological processes by binding to a family of G protein–coupled receptors or as an intracellular second messenger. Mammalian S1P phosphatase (SPP-1), which degrades S1P to terminate its actions, was recently cloned based on homology to a lipid phosphohydrolase that regulates the levels of phosphorylated sphingoid bases in yeast. Confocal microscopy surprisingly revealed that epitope-tagged SPP-1 is intracellular and colocalized with the ER marker calnexin. Moreover, SPP-1 activity and protein appeared to be mainly enriched in the intracellular membranes with lower expression in the plasma membrane. Treatment of SPP-1 transfectants with S1P markedly increased ceramide levels, predominantly in the intracellular membranes, diminished survival, and enhanced apoptosis. Remarkably, dihydro-S1P, although a good substrate for SPP-1 in situ, did not cause significant ceramide accumulation or increase apoptosis. Ceramide accumulation induced by S1P was completely blocked by fumonisin B1, an inhibitor of ceramide synthase, but only partially reduced by myriocin, an inhibitor of serine palmitoyltransferase, the first committed step in de novo synthesis of ceramide. Furthermore, S1P, but not dihydro-S1P, stimulated incorporation of [3H]palmitate, a substrate for both serine palmitoyltransferase and ceramide synthase, into C16-ceramide. Collectively, our results suggest that SPP-1 functions in an unprecedented manner to regulate sphingolipid biosynthesis and is poised to influence cell fate.

scholarly journals Sphingolipid-Induced Programmed Cell Death Is a Salicylic Acid and EDS1-Dependent Phenotype in Arabidopsis

2021 ◽  
Author(s):  
Stefanie Koenig ◽  
Jasmin Goemann ◽  
Agnieszka Zienkiewicz ◽  
Krzysztof Zienkiewicz ◽  
Dorothea Meldau ◽  
...  
Keyword(s):  
Cell Death ◽  
Salicylic Acid ◽  
Programmed Cell Death ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Triple Mutant ◽  
A Cell ◽  
P Fraction ◽  
Chain Lengths ◽  
Cell Death Phenotype

Ceramides and long chain bases (LCBs) are plant sphingolipids involved in the induction of plant programmed cell death (PCD). The fatty acid hydroxylase mutant fah1 fah2 exhibits high ceramide levels and moderately elevated LCB levels. Salicylic acid (SA) is strongly induced in these mutants, but no cell death is visible. To determine the effect of ceramides with different chain lengths, fah1 fah2 was crossed with ceramide synthase mutants longevity assurance gene one homologue1-3 (loh1, loh2 and loh3). Surprisingly, only triple mutants with loh2 show a cell death phenotype under the selected conditions. Sphingolipid profiling revealed that the greatest differences between the triple mutant plants are in the LCB and LCB-phosphate (LCB-P) fraction. fah1 fah2 loh2 plants accumulate LCB d18:0 and LCB-P d18:0. Crossing fah1 fah2 loh2 with the SA synthesis mutant sid2-2, and with the SA signaling mutants enhanced disease susceptibility 1-2 (eds1-2) and phytoalexin deficient 4-1 (pad4-1), revealed that lesions are SA- and EDS1-dependent. These quadruple mutants also suggest that there may be a feedback loop between SA and sphingolipid metabolism as they accumulated less ceramides and LCBs. In conclusion, PCD in fah1 fah2 loh2 is a SA and EDS1-dependent phenotype, which is likely due to accumulation of LCB d18:0.

scholarly journals A Dansyl-Modified Sphingosine Kinase Inhibitor Dpf-543 Enhanced de Novo Ceramide Generation

2021 ◽  
Author(s):  
Maftuna Shamshiddinova ◽  
Shokhid Gulyamov ◽  
Hee Jung Kim ◽  
Seo Hyeon Jung ◽  
Dong Jae Baek ◽  
...  
Keyword(s):  
Cancer Metastasis ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Sphingosine Kinase ◽  
Acid Sphingomyelinase ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Serine Palmitoyltransferase ◽  
Comparative Efficiency ◽  
Sphingosine 1 Phosphate

Sphingosine-1-phosphate (S1P) synthesized by sphingosine kinase (SPHK) is a signaling molecule, involved in cell proliferation, growth, differentiation, and survival. Indeed, a sharp increase of S1P was linked to the pathological outcome with inflammation, cancer metastasis or angiogenesis etc. In this regard, the SPHK/S1P axis regulation has been a specific issue in anticancer strategy to turn accumulated sphingosine (SPN) into cytotoxic ceramides (Cers). For these purposes, there have been numerous chemicals synthesized for SPHK inhibition. In this study, we investigated the comparative efficiency of dansylated PF-543 (DPF-543) on the Cers synthesis along with PF-543. DPF-543 deserved attention in strong cytotoxicity, due to the cytotoxic Cers accumulation by ceramide synthase (CerSs). DPF-543 exhibited dual actions on Cers synthesis by enhance the serine palmitoyltransferase (SPT) activity, and by inhibiting SPHKs which eventually induced an unusual environment of the high amount of 3-ketosphinganine and sphinganine (SPA). SPA in turn was consumed to synthesize Cers via de novo pathway. Interestingly, PF-543 increased only the SPN level, but not for SPA. In addition, DPF-543 mildly activates acid sphingomyelinase (aSMase) that contributes a partial increase on Cers. Collectively, a dansyl-modified DPF-543 relatively en-hanced Cers accumulation via de novo pathway which was not observed in PF-543. Our results demonstrated that the structural modification on SPHK inhibitors is still an attractive anticancer strategy by regulating sphingolipid metabolism.

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