Add time:07/22/2019         Source:sciencedirect.com

Publisher SummaryThe reaction covered by this article is ceramide + phosphatidylethanolamine → 1-O-acylceramide + lysophosphatidylethanolamine. The emergence of ceramide as a potentially important cellular messenger has led to a renewal of attention in the metabolism of this lipid. This interest has included studies on the pharmacology of compounds, some structurally analogous to ceramide, which result in changes in endogenous cellular ceramide concentrations. 1-Phenyl-2-decanoylamino-3-morpholino-l-propanol (PDMP) is one such inhibitor. The D-threo enantiomer of PDMP specifically blocks glucosylceramide synthase, resulting in the depletion of cell glucosylceramide and more complex glucosylceramidebased glycosphingolipids. Early work with this inhibitor revealed that, in the presence of PDMP, cell ceramide levels would increase in parallel with glucosylceramide depletion. This observation led to the interpretation that ceramide, a substrate for the cerebroside synthase, increased because of inhibition of the cerebroside synthase. However, the development of more active homologs of PDMP and studies on the enantiomers of these compounds that were inactive against glucosylceramide synthase demonstrated that erythro diastereomers could raise cell ceramide levels at concentrations equivalent to those for threo diastereomersfl. In addition, aliphatic homologs of PDMP, 1-morpholino-1-deoxyceramides, demonstrated activity against the glucosylceramide synthase with little effect on ceramide concentrations. These observations led to the conclusion that PDMP-mediated changes in cell ceramide concentrations were the result of an activity at a second, uncharacterized site. Attempts to identify this second site of action by screening for inhibitory or stimulatory effects of erythro and threo diastereomers of PDMP homologs on known enzymes of ceramide metabolism were unsuccessful. Specifically, no effects were observed on ceramidase, sphingomyelinase, sphingomyelin synthase, or ceramide synthase activities. An alternative strategy was then employed. Cultured MDCK cells were incubated with N-acetyl-[3-3H]sphingosine. Under these conditions, a nonpolar product was observed, subsequently demonstrated to be 1-O-acylceramide. This chapter describes the characterization of this product, its anabolic pathway, and the purification and characterization of 1-O-acylceramide synthase.

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