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Title

Specificity of the dihydroceramide desaturase inhibitor N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide (GT11) in primary cultured cerebellar neurons

AuthorsTriola Guillem, Gemma ; Fabriàs, Gemma ; Dragusin, Mihaela; Niederhausen, Lars; Broere, Roland; Llebaria, Amadeu ; Van Echten-Deckert, Gerhild
KeywordsDihydroceramide desaturase inhibitor
GT11
Primary cultured cerebellar neurons
Cell growth regulation
Issue Date15-Sep-2004
PublisherAmerican Society for Pharmacology and Experimental Therapeutics
CitationMolecular Pharmacology 66(6): 1671-1678 (2004)
AbstractDihydroceramide desaturase catalyzes the conversion of the innocuous precursor dihydroceramide into a highly bioactive product ceramide. We studied the effect of N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide (GT11), the first inhibitor of this enzyme, in primary cultured cerebellar neurons. Although desaturase was efficiently inhibited (IC50 of 23 nM), the compound lost its specificity at higher concentrations. From 5 µM upward, GT11 also decreased de novo sphingolipid biosynthesis. Studies with two differentially labeled radioactive analogs of GT11 support that the inhibitor itself and not a downstream metabolic product, interferes with sphingolipid biosynthesis. It is interesting that serine palmitoyltransferase activity decreased in the presence of high concentrations of GT11 in intact cells, but not when added directly into cell homogenates. However, suppression of enzyme transcription could not be detected. But at high concentrations GT11 provoked an accumulation of sphingosine-1-phosphate and especially of dihydrosphingosine-1-phosphate, suggesting a decreased activity of sphingosine-1-phosphate lyase. Enzyme activity measurements indeed supported this assumption. Thus, at higher concentrations, GT11 interferes with lyase activity, inducing an accumulation of sphingoid base phosphates that, in turn, down-regulate serine palmitoyltransferase activity. At low concentrations, however, GT11 is the first specific inhibitor of dihydroceramide desaturase described so far. Considering the proapoptotic and proinflammatory effect of ceramide, GT11 could also turn out to be a novel cell-protective agent.
Description8 pages, 9 figures.-- PMID: 15371559 [PubMed].-- Printed version published Dec 2004.
Publisher version (URL)http://dx.doi.org/10.1124/mol.104.003681
URIhttp://hdl.handle.net/10261/17898
DOI10.1124/mol.104.003681
ISSN0026-895X
E-ISSN1521-0111
Appears in Collections:(IQAC) Artículos
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