Ceramides

SILVIA VAENA DE AVALOS, JEFFREY A. JONES AND YUSUF A. HANNUN  

Medical University of South Carolina, Charleston, South Carolina, USA 

Sphingosine D-eryihro-sphingosine (25,3/J,4 )-2-ainino-l,3-dihydroxy-octadec-4-ene 

Dihydrosphingosine D-eryihro-dihydrosphingosine (25,3/J)-2-amino-1,3-dihydroxy-octadecane 

0dihydroceramide desaturase dihydroceramide hydroxylase dihydroceramide hydroxylase ceramidase dihydroceramidase phytoceramidase 

---

Glycohpids (5,14) are primarily glycosphingoHpids, molecules that have oligosaccharide groups attached to ceramide [104404-17-3]. They are present, at least in small amounts, in the membranes of most, if not all, tissues. They too, like cell-membrane glycoproteins, are recognition deterrninants. 

FIGURE8.il Formation of an amide linkage between a fatty acid and sphingosine produces a ceramide. 

FIGURE 25.25 Biosynthesis of sphingolipids in animals begins with the 3-ketosphinga-nine synthase reaction, a PLP-dependent condensation of palmitoyl-CoA and serine. Subsequent rednction of the keto group, acylation, and desatnration (via rednction of an electron acceptor, X) form ceramide, the precnrsor of other sphingolipids. 

FIGURE 25.26 Glycosylceramides (such as galactosylceramide), gangUosides, and sphingomyelins are synthesized from ceramide in animals. 

Lipid phosphate phosphohydrolases (LPPs), formerly called type 2 phosphatidate phosphohydrolases (PAP-2), catalyse the dephosphorylation of bioactive phospholipids (phosphatidic acid, ceramide-1-phosphate) and lysophospholipids (lysophosphatidic acid, sphingosine-1-phosphate). The substrate selectivity of individual LPPs is broad in contrast to the related sphingosine-1-phosphate phosphatase. LPPs are characterized by a lack of requirement for Mg2+ and insensitivity to N-ethylmaleimide. Three subtypes (LPP-1, LPP-2, LPP-3) have been identified in mammals. These enzymes have six putative transmembrane domains and three highly conserved domains that are characteristic of a phosphatase superfamily. Whether LPPs cleave extracellular mediators or rather have an influence on intracellular lipid phosphate concentrations is still a matter of debate. 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

The Noyori procedure was applied to a total synthesis of baiyunoside, a sweet principle, using 2,3,4-tri-<9-benzyl-D-xylopyranosyl fluoride (18 see Table 1), and a synthesis of glycotriosyl ceramide. A model experiment for the synthesis, using 18, showed a solvent dependence for the a ratio of the products. In this case, the use of acetonitrile, oxolane, or ether gave the a anomer (1,2-a.v), and the use of toluene or hexane gave the P anomer (1,2-trans), preponderantly. 

The major glycohpids found in animal tissues are glycosphingohpids. They contain ceramide and one or more sugars. Galactosylceramide is a major glyco-... 

Sphingomyelins (Figure 14—11) are phosphohpids and are formed when ceramide reacts with phos-phatidylchohne to form sphingomyelin plus diacylglyc-erol (Figure 24-8A). This occurs mainly in the Golgi apparatus and to a lesser extent in the plasma membrane. 

GlycosphingoMpids Are a Combination of Ceramide With One or More Sugar Residues... 

---