Biosynthesis of ceramides

Tanno, O. et al., Nicotinamide increases biosynthesis of ceramides as well as other stratum corneum lipids to improve the epidermal permeability barrier, Br. J. Dermatol., 143, 524, 2000. 

Inhibitors of the enzymes that participate in the de novo biosynthesis of ceramide may be used to treat pathologies associated with elevated intracellular ceramide levels, such as chemotherapy-induced cell death and insulin resistance in muscle. 

Inhibition of dihydroceramide desaturase. The last enzyme in the de novo biosynthesis of ceramide is inhibited by GT-11, but at high concentrations this compound also inhibited SIP lyase and SPTase (147, 148). Fenretinide (4-HPR, Fig. 12) also inhibited dihydroceramide desaturase (147, 148). This synthetic retinoid and its analogs have apoptogenic activity, which elevates intracellular ceramide levels and induces cell death in a variety of cell types in vitro and in vivo by multiple mechanisms (117, 149, 150). 

Zabin, I. Biosynthesis of ceramide by rat-brain homogenates. J. Amer. chem. Soc. 79, 5834 (1957). 

Ceramide is generated de nooo in the endoplasmic reticulum. The first step in the biosynthesis of ceramide is the condensation of L-serine and palmitoyl-CoA, a reaction catalyzed by serine palmitoyltransferase. The condensation product obtained is 3-ketosphinganine (Fig. 3.10), and this reaction is considered as the rate-limiting enzyme in sphingolipid synthesis. ... 

From experiments with CoA-activated fatty acids, Braun et al. (1970) concluded that the system responsible for the biosynthesis of ceramide is the one first suggested by Sribney (1966). Fatty acid is tied to a long-chain base by an acyltransferase, using fatty acyl-CoA as substrate. The authors also suggested that the specificity of the acyl-CoA sphingosine N-acyl transferase controls the distribution of the constituent fatty acids in ceramides. 

For some time these two reactions were believed to be entirely responsible for the biosynthesis of ceramide galactoside. It has been as-suin( d that ceramide giucoside is formed by a similar series of reactions where fJDP glucose substituted for UDP galactose. 

The biosynthesis of ceramide trihexoside by spleen microsomes has been described (Hildebrand and Hauser, 1969). These authom reported upon the ceramide lactoside-stimulated inconioration of galacto.se- C from UDP gaIactose- C into a product which appeared to have the properties of ceramide trihexoside. 

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. 

Because membranes components participate in nearly every cell activity their structures are also dynamic and far from the equilibrium states that are most readily understood in biophysical terms. Newly synthesized bilayer lipids are initially associated with endoplasmic reticulum (Ch.3) whereas phospholipids initially insert into the cytoplasmic leaflet while cholesterol and sphingolipids insert into the luminal endoplasmic reticulum (ER) leaflet. Glycosylation of ceramides occurs as they transit the Golgi compartments, forming cerebrosides and gangliosides in the luminal leaflet. Thus, unlike model systems, the leaflets of ER membranes are asymmetric by virtue of their mode of biosynthesis. 

Merrill, A.H.Jr., and Wang, E, 1992, Enzymes of ceramide biosynthesis. Methods Enzymol. 209 427-437. 

Effect of Ceramides on Phospholipid Biosynthesis and Its Implication for Apoptosis... 

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