Sulfatide metabolism

Sundaram KS, Fan JH, Engelke JA, FoleyAL, Suttie JW, and Lev M (1996) Vitamin K status influences brain sulfatide metabolism in young mice and rats. Journal of Nutrition 126, 2746-51. 

Two enzymes have activities related to the metabolism of sulfatides a sulfatase, which is capable of hydrolyzing sulfatides to yield cerebroside and sulfate, and a sulfatide synthetase, which catalyzes the formation of cerebroside and a sulfate donor (phosphoa-denosine phosphosulfate). The exact role of these enzymes in the overall sulfatide metabolism is not clear. A galactosylglucosyl ceramide esterfied with sulfuric acid in position 3 of the galactose has been found in kidney. The dihexose ceramide sulfatide is believed to be synthesized from the neutral ceramide in presence of phosphoadenosine phosphosulfate. The synthetase is a microsomal enzyme. The sulfatase is believed to be a lysosomal enzyme. 

Myelin components exhibit great heterogeneity of metabolic turnover. One of the novel characteristics of myelin demonstrated in early biochemical studies was that its overall rate of metabolic turnover is substantially slower than that of other neural membranes [1]. A standard type of experiment was to evaluate lipid or protein turnover by injecting rat brains with a radioactive metabolic precursor and then follow loss of radioactivity from individual components as a function of time. Structural lipid components of myelin, notably cholesterol, cerebro-side and sulfatide, as well as proteins of compact myelin, are relatively stable, with half-lives of the order of many months. One complication in interpreting these studies is that the metabolic turnover of individual myelin components is multiphasic - consisting of an initial rapid loss of radioactivity followed by a much longer slower loss. 

Familial demyelinative/dysmyelinative and axonal neuropathies may also be caused by impaired lysosomal lipid metabolism. Metachromatic leukodystrophy (sulfatide lipidosis) results from mutations of the arylsulfatase A gene, which encodes a lysosomal enzyme required for sulfatide turnover. Myelin is affected in both CNS and PNS, though dysfunction is restricted to the PNS in some patients, and the onset of symptoms can occur at any time between infancy and adulthood. Bone marrow transplantation can slow disease progression and improve nerve conduction velocities [57]. (See in Ch. 41.)... 

Myelin is approximately 75% lipid and 25% protein. Carbohydrate residues are associated with both the lipid and the protein components of myelin. High proportions of cholesterol, phospholipid, and glycolipid are found in the lipid fractions. Phospholipids include ethanolamine phosphatides, phosphatidylserine, and phosphatidylinositol glycolipids include both neutral (cerebroside, sulfatide, galactosyldiglyceride) and polar (gangliosides, especially GMj and GMJ lipids. A classification and discussion of the metabolism of brain lipids is beyond the scope of this article readers are referred to Lajtha (1969), Davison (1968), Awasthi and Srivastava (1980), and Suzuki (1981). 

It seems that a large proportion of adult rat, rabbit, or chicken brain cholesterol undergoes very slow metabolism. Since about 70% of brain cholesterol is located in the myelin sheath, it is probable that at least part of this structure is metabolically a relatively stable tissue component. Other studies on brain lipids support this view. Thus distribution of rat brain cerebroside sulfate is similar to that of cholesterol and turnover of sulfatide is also exceedingly slow. Furthermore, Davison and Gregson (1962) found that persisting radioactivity was associated primarily with the myelin fraction prepared from brains of rats previously injected with S -sulfate or methionine. 

A variety of pathways has been suggested for the metabolism of sulfatides, any of which could be impaired in ML. It has been proposed that galacto-cere-broside acts as a precursor for sulfatide (Radin et al. 1957 Hauser 1964) with phosphoadenosine-phosphosulfate (PAPS) as sulfate donor (Goldberg 1961) according to the following formula Galactocerebroside + PAPS = sulfatide + PAP (McKhann et al. 1965 Balasubramanian and Bachhawat 1963, 1964). 

In a more recent paper, Svennerholm s group (Martensson et al. 1966) has reviewed the subject and has interpreted the available data on the metabolic interrelationship between cerebrosides and sulfatides according to the following scheme ... 

Fig. 3. Relationship between the metabolism of cerebrosides and sulfatides. From a) Jatzkewitz (1960), b) Hauser (1964), c) Brady (1964). Block in lower arrow indicates the site of the possible lesion in...

It is not known whether glial cells become abnormal because of glial insufficiency (ScHOLZ 1925) resulting from excessive myelin degradation which exceeds the metabolic capacity of glial cells (Peiffer 1959) in the presence of a normal enzymic machinery or because they, too, harbour the enzymic lesion. It is more likely, that the enzymic lesion in ML is not limited to certain cells (Jatzkewitz 1960) but plays a role wherever sulfatides are important substrates. 

Moser, H. W., and M. Lees Sulfatide lipidosis Metachromatic leukodystrophy. In The metabolism of inherited disease, p. 539. Eds J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson. New York McGraw-Hill Book Company 1966. 

The adenosine-3 -phosphate-5 -phosphosulfate (PAPS) generating system could be located in the 105,000 g supernatant of rat brain, whereas the Gal-Cer sulfotransferase remained particle bound. Substrate may be Gal-Cer or lactosyl ceramide. Sulfatides of kidney show a higher metabolic turnover than those in brain. Water-soluble sulfatide, discovered in the 105,000 g supernatant of a brain homogenate, was found to be complexed to certain specific proteins (Hersch-kowitz et al., 1968). It was postulated that this might represent a transport form from the site of biosynthesis to the myelin. 

The metabolism of sulfatide has been of some clinical interest since this material accumulates in nervous tissue of patients affected with metachromatic leukodystrophy (Jatzkewitz, 1958 Austin, 1959 Ilagberg et al., 1962). Several arylsulfatases have been detected in tissues and have been referred to as A, B, and C. The absence of aryisulfatase A had been noted in pathological tissue samples (Austin el al., 1963 Mehl and Jatzke-... 

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