Cerebroside, biosynthesis

From evidence available it seems most likely that the basic disturbance in GD is located at some enzymatic step in cerebroside biosynthesis or breakdown (see figure 7). According to present knowledge, cerebrosides are normally formed from larger glycosphingolipids, the majority of which may originate in red cells. Increased formation from these precursors may result from deletion of normal feedback control on the other hand accumulation of cerebrosides may result from a decreased rate of catabolism. 

In an earlier report Brady (1962) suggested the formation of cerebroside by acylation of psychosine with acyl-CoA. However, observations of other investigators indicate that the cerebroside biosynthesis mainly proceeds via acylation of sphingosine followed by transfer of the monosaccharide (pathway II) (Hauser, 1967 Kanfer, 1969 Morell and Radin, 1969, 1970a). 

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. 

FIGURE 21-31 Biosynthesis of sphingolipids. Condensation of palmitoyl-CoA and serine followed by reduction with NADPH yields sphinganine, which is then acylated to N-acylsphinganine (a ceramide). In animals, a double bond (shaded pink) is created by a mixed-function oxidase, before the final addition of a head group phosphatidylcholine, to form sphingomyelin glucose, to form a cerebroside. 

The diseases considered here affect only a small fraction of the problems in the catabolism of body constituents. On the other hand, fewer cases are on record of deficiencies in biosynthetic pathways. These are more often absolutely lethal and lead to early spontaneous abortion. However, blockages in the biosynthesis of cerebrosides are known in the special strains of mice known as Jimpy, Quaking, and msd (myelin synthesis deficient).377 378 The transferases (points 11 and 12 of Fig. 20-11) are not absent but are of low activity. The mice have distinct neurological defects and poor myelination of nerves in the brain. 

Sphingolipids comprise glycolipids (gangliosides and cerebrosides) and the phospholipid, sphingomyelin. These compounds, too, are important membrane constituents. The biosynthesis of sphingolipids involves the common intermediate ceramide (Fig. 13-15). 

Several cases of a new form of metachromatic leukodystrophy have been reported (Hahn et al., 1981, 1982 Inui et al., 1983). These cases have clinical symptoms resembling juvenile metachromatic leukodystrophy, but have only about half of the normal arylsulfohydrolase A activity in leukocytes and fibroblasts. The kinetic properties of the arylsulfohydrolase A from fibroblasts are normal. However, the cerebroside 3-sulfate loading test (Porter et al., 1971a) with growing fibroblasts shows an abnormal response, indicating a disturbance in arylsulfatase A activity. Supplementation with the activator (Stevens et al., 1981) of arylsulfatase A results in a normal cerebroside 3-sulfate loading test. This indicates that the new form of metachromatic leukodystrophy is not caused by the deficiency of arylsulfohydrolase A, but rather is caused by a deficiency of the activator protein (Shapiro et al., 1979). Fujibayashi and Wenger (1986) have studied the biosynthesis of sulfa-tide/GMj activator protein in control and mutant cultured skin fibroblasts. Their results indicate that patients with variant form of metachromatic leu-... 

Structurally related cerebrosides asperiamides B (198) and C (199) were obtained from A. nigerMF-16, which was isolated from seawater collected in Quanzhou Gulf, China, together with two known intermediates of aflatoxin biosynthesis, averufm and nidurufin/ ° The latter compounds displayed moderate antiviral activity against tobacco mosaic virus, while 198 and 199 were inactive. 

Fig. 33.34. The synthesis of 3 -phosphoadenosine 5 -phosphosulfate (PAPS), an active sulfate donor. PAPS donates sulfate groups to cerebrosides to form sulfatides and is also involved in glycosaminoglycan biosynthesis (see Chapter 49). Ad = adenosine.

L.L. Sarlieve, R. Bouchon, C. Koehl and N.M. Neskovic, Cerebroside and sulfatide biosynthesis in the brain of Snell Dwarf mouse effects of thyroxine and growth hormone in the early postnatal period, J. NeurochCTi. 40 1058 (1983). 

The biochemical buildup of the brain is far from complete at birth, and the biosynthesis of brain lipids is essential to the proper development of the child. Among the lipids found in brain are gangliosides, cerebrosides, and sphingomyelins. The synthesis of these lipids assumes particular importance when the nerve... 

Now it seems established that the biosynthesis of cerebrosides occurs in two distinct steps. A brain or spleen microsomal enzyme catalyzes the first the reaction of sphingosine and UDP-galactose to yield UDP and galactopsychosine. A second enzyme, about which little is known, catalyzes the reaction between the galactopsychosine and a fatty acyl-CoA to yield Co ASH and galactocerebroside (see Fig. 3-36). 

Curtino Caputto, 1972). These reactions offer the possibility of an alternative pathway for the biosynthesis of cerebrosides. 

Burton, Sodd and Brady (1958) employed a crude system from rat brain for the investigation of the biosynthesis of cerebroside. The assay employed was the incorporation of radioactivity from galactose-1- C into cerebroside. The... 

Biosynthesis of odd- and even-numbered cerebroside fatty acids Evidence for two... 

Isotopic studies of the biosynthesis of the cerebroside fatty acids in rats. J. Lipid Res. 

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