Dihydroceramide desaturase and dihydrosphingolipids: Debutant players in the sphingolipid arena

Fabriás, Gemma; Munoz-Olaya, Jose; Cingolani, Francesca; Signorelli, Paola; Casas, Josefina; Gagliostro, Vincenzo; Ghidoni, Riccardo

doi:10.1016/j.plipres.2011.12.002

Cited by 86 publications

(82 citation statements)

References 133 publications

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“…However, the occurrence of inhibition in cell lysates is against the involvement of reactive oxygen species. Another possibility is that SKI II inhibits CB5R, the other enzyme present in the electron transport chain associated to Des1 activity ( 34 ). Although this possibility has not been experimentally assessed, it is supported by the molecular modeling studies described above, which showed similar results in the docking to CB5R of SKI II and the known CB5R inhibitors luteolin, quercetin, and (+)-taxifolin ( Fig.…”

Section: Discussionmentioning

confidence: 78%

“…Several studies have reported on the induction of autophagy by treatment with drugs that increase dhCer levels, such as fenretinide, resveratrol, and ␥ -tocopherol ( 34 ). Moreover, we previously reported on the induction of autophagy with prior increase in dhCer by the Des1 inhibitor, XM462, in HGC 27 cells ( 66 ).…”

Section: Discussionmentioning

confidence: 79%

“…Blockade of Des1 produces an increase in dihydroceramides (dhCers), which have emerged as bioactive lipids and the target of several drugs ( 34 ), including fenretinide. Several studies have shown that cells respond to fenretinide treatment with a robust production of dhCers (35)(36)(37)(38)(39)(40)(41)(42)(43)(44), and that this increase induces autophagy ( 45,46 ).…”

Section: Des1 Enzyme Assaymentioning

confidence: 99%

“…Cell lysis was performed with [30][31][32][33][34][35][36][37][38][39][40] l of lysis buffer [150 mM NaCl, 1% Igepal-CA630, 50 mM TrisHCl (pH 8), 2 g/ml aprotinin, 5 g/ml leupeptin, and 1 mM PMSF] by three cycles of bath sonication (5 s)/rest on ice (10 s). Then samples were kept on ice for 30 min and centrifuged for 3 min at 10,000 rpm.…”

Section: Western Blottingmentioning

confidence: 99%

“…Other Des1 inhibitory compounds produced competitive (GT11, K i = 6 M) ( 74 ) or mixed-type inhibition (XM462, K i = 2 M) ( 47 ), while fenretinide functions as a competitive inhibitor ( K i = 8 M) at short incubation times and as an irreversible inhibitor at long incubation times ( 40 ). While GT11 and XM462 are structural analogs of the Des1 substrate, fenretinide and other Des1 inhibitors ( 34 ) are not. We hypothesize that, while the structural analogs interact with the terminal desaturase protein, the nonstructural analogs act on other components of the electron transport chain or, alternatively, affect Des1 activity by modifying the redox status of well as polar interactions with F300.…”

Section: Molecular Dockingmentioning

confidence: 99%

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Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Cingolani

Casasampere

Sanllehí

et al. 2014

Journal of Lipid Research

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proapoptotic sphingosine (So) and ceramide (Cer). Thus, as central enzymes in modulating the Cer/S1P balance, SKs are attractive targets for cancer therapy ( 1 ). Two SKs exist in humans, SK1 and SK2. SK1 has been extensively studied and there is a large body of evidence that proves its role in promoting cell survival, proliferation, and neoplastic transformation ( 2-5 ). SK1 is also elevated in many human cancers, which appears to contribute to carcinogenesis, chemotherapeutic resistance, and poor patient outcome. SK2, however, has not been as well-characterized, and there are contradictions in the key physiological functions that have been proposed for this isoform. Despite this, many studies are now emerging that implicate SK2 in key roles in a variety of diseases, including the development of a range of solid tumors ( 6 ).The potential of SKs as therapeutic targets has boosted the development of small molecule inhibitors ( 4,(7)(8)(9)(10)(11)(12)(13)(14). A detailed characterization of their pharmacology, particularly their selectivity against human SK1 and SK2, has been published ( 15 ). The fi rst known SK inhibitors were long chain base analogs such as N , N -dimethyl-D-erythro-sphingosine (DMS) ( 16,17 ) and L-threo-dihydrosphingosine (safi ngol) ( 18-21 ). While DMS inhibits both SK1 and SK2 by (SGR 2009(SGR 1072, and the Fundació la Marató de TV3 (112130 and 112132 Abbreviations: CB5R, NADH-cytochrome b5 reductase; C16dhCer, N -hexadecanoyldihydrosphingosine ; CDH, ceramide dihexoside (lactosylceramide); Cer, ceramide; CerC6NBD, N -[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl]-D-erythro-sphingosine; CMH, ceramide monohexoside (glucosyl and galactosylceramide); Des1, dihydroceramide desaturase; dhCDH, dihydroceramide dihexoside (lactosyldihydroceramide); dhCer, dihydroceramide; dhCerC6NBD, N -[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl]-D-erythro-dihydrosphingosine; dhSM, dihydrosphingomyelin; DMS, N , N -dimethyl-D-erythro-sphingosine; FAD, fl avin adenine dinucleotide; LC3, microtubule-associated protein 1-light chain 3; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; NBD, 4-nitro-2,1,3-benzoxadiazole; PDB, Protein Data Bank; S1P, sphingosine-1-phosphate; SK, sphingosine kinase; SKI, sphingosine kinase inhibitor; So, sphingosine; TBST, TBS with 0.1% Tween 20; UPLC, ultraperformance LC . This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2011-22444), the Generalitat de Catalunya

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 79%

Section: Des1 Enzyme Assaymentioning

confidence: 99%

Section: Western Blottingmentioning

confidence: 99%

Section: Molecular Dockingmentioning

confidence: 99%

See 3 more Smart Citations

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Cingolani

Casasampere

Sanllehí

et al. 2014

Journal of Lipid Research

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Flavonoids as putative modulators of Δ4‐, Δ5‐, and Δ6‐desaturases: Studies in cultured hepatocytes, myocytes, and adipocytes

et al. 2018

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This study was conducted to screen flavonoids for affecting expression of desaturases involved in omega-3 fatty acid synthesis and ceramide (CER) metabolism. To this end, cultured HepG2 hepatocytes, C2C12 myocytes, and 3T3-L1 adipocytes were treated with nontoxic concentrations of 12 selected flavonoids and expression of Δ4-, Δ5-, and Δ6-desaturases (DEGS1, FADS1, and FADS2, respectively) was determined. The flavonoids tested were more cytotoxic to HepG2 and 3T3-L1 than to C2C12 cells. In HepG2 cells, FADS1 was induced by quercetin and FADS2 expression was increased by daidzein, genistein, and pratensein treatment. DEGS1 was increased by apigenin, luteolin, orobol, and quercetin administration. In differentiated C2C12 cells, substances had no inducing effect or even lowered target gene expression. Pratensein induced both FADS1 and FADS2 in differentiated 3T3-L1 cells and DEGS1 was increased by treatment with apigenin, genistein, luteolin, orobol, and quercetin. In conclusion, pratensein may be an interesting test compound for further studies in vitro and in vivo on omega-3 synthesis since it induces its rate-limiting enzyme FADS2. Apigenin, luteolin, orobol, and quercetin induced DEGS1 and thereby possibly synthesis of proapoptotic CER in malignant HepG2 cells and 3T3-L1. In contrast, in benign C2C12 cells, they did not elevate mRNA steady state levels of DEGS1. That may partly explain the higher resistance of C2C12 cells against flavonoids compared to the other cell lines. By affecting tumor cells and nontumor cells differently, these flavonoids may be promising substances for further research regarding anticancer properties. © 2018 BioFactors, 44(5): [485][486][487][488][489][490][491][492][493][494][495] 2018

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Asymmetric Synthesis and Binding Study of New Long‐Chain HPA‐12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT

Ďuriš

Daı̈ch

Santos

et al. 2016

Chemistry A European J

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A series of 12 analogues of the Cer transfer protein (CERT) antagonist HPA-12 with long aliphatic chains were prepared as their (1R,3S)-syn and (1R,3R)-anti stereoisomers from pivotal chiral oxoamino acids. The enantioselective access to these intermediates as well as their ensuing transformation relied on a practical crystallization-induced asymmetric transformation (CIAT) process. Sonogashira coupling followed by triple bond reduction and thiophene ring hydrodesulfurization (HDS) into the corresponding alkane moieties was then implemented to complete the synthetic routes delivering the targeted HPA-12 analogues in concise 4- to 6-step reaction sequences. Ten compounds were evaluated regarding their ability to bind to the CERT START domain by using the recently developed time-resolved FRET-based homogeneous (HTR-FRET) binding assay. The introduction of a lipophilic appendage on the phenyl moiety led to an overall 10- to 1000-fold enhancement of the protein binding, with the highest effect being observed for a n-hexyl residue in the meta position. The importance of the phenyl ring for the activity was indicated by the reduced potency of the 3-deoxyphytoceramide aliphatic analogues. The 1,3-syn stereoisomers were systematically more potent than their 1,3-anti analogues. In silico studies were used to rationalized these trends, leading to a model of protein recognition coherent with the stronger binding of (1R,3S)-syn HPAs.

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Dihydroceramide desaturase and dihydrosphingolipids: Debutant players in the sphingolipid arena

Cited by 86 publications

References 133 publications

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Flavonoids as putative modulators of Δ4‐, Δ5‐, and Δ6‐desaturases: Studies in cultured hepatocytes, myocytes, and adipocytes

Asymmetric Synthesis and Binding Study of New Long‐Chain HPA‐12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT

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