Myelin biosynthesis

D Urso, D., Brophy, P. J., Staugaitis, S. M. etal. Protein zero of peripheral myelin biosynthesis, membrane insertion, and evidence for homotypic interactions. Neuron 4 449 60,1990. 

Organotellurium compounds such as dimethyltellurium dichloride and dimethyltelluride have been reported as potential inhibitors of squalene monooxygenase, causing a dramatic reduction in the rate of cholesterol biosynthesis and leading to degradation of the myelin sheath. 

On the other hand, as we have already seen, cholesterol tends to reduce the mobility of molecules in membranes and causes phospholipid molecules to occupy a smaller area than they would otherwise. Myelin is especially rich in long-chain sphingolipids and cholesterol, both of which tend to stabilize artificial bilayers. Within our bodies, the bilayers of myelin tend to be almost solid. Bilayers of some gram-positive bacteria growing at elevated temperatures are stiffened by biosynthesis of bifunctional fatty acids with covalently joined "tails" that link the opposite sides of a bilayer.149... 

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. 

Neurological complications also are associated with vitamin B-12 deficiency and result from a progressive demyelination of nerve cells. The demyelination is thought to result from the increase in methylmalonyl-CoA that result from vitamin B-12 deficiency. Methylmalonyl-CoA is a competitive inhibitor of malonyl-CoA in fatty acid biosynthesis as well as being able to substitute for malonyl-CoA in any fatty acid biosynthesis that may occur. Since the myelin sheath is in continual flux the methylmalonyl-CoA-induced inhibition of fatty acid synthesis results in the eventual destruction of the sheath. The incorporation methylmalonyl-CoA into fatty acid biosynthesis results in branched-chain fatty acids being produced that may severely alter the architecture of the normal membrane structure of nerve cells... 

On the above view, NLSD is primarily a disease of defective phospholipid metabohsm and the TAG-derived route of phospholipid biosynthesis is essential for the normal functioning of skin, muscle, liver, and the central nervous system. Further studies on the fatty hver dystrophic mouse which bears a close resemblance to human NLSD [103] may identify fhe defective gene. Defective neutral phospholipid metabolism in this mouse model is reflected by a decreased phosphohpid content of peripheral nerve myelin [109]. The nature of the hpase(s) involved in normal TAG-to-phospholipid acyltransfer has not been characterized, but may be similar to a previously described microsomal neutral hpase [110] or to a carboxylesterase [111]. 

Vitamin B12 (2 a) participates in the aqueous-phase biosynthesis of purine and pyrimidine bases, the reduction of ribonucleotide triphosphates, the conversion of methylmalonyl-coenzyme A to succinyl-coenzyme A, the biosynthesis of methionine from homocysteine, and the formation of myelin sheath in the nervous systems. 

Essentially similar results have been obtained by Eylar and co-workers " on the biosynthesis of bovine submaxillary mucin. The enzyme is firmly bound to a membrane solubilization by Triton X-100 results in a large increase in enzymic activity." The enzyme was purified by gel filtration, and its properties were studied. Among various substances studied, the only one (besides carbohydrate-free mucins) that was active as the acceptor of 2-acetamido-2-deoxy-D-galactose was a basic protein, called encephalitogen, isolated from bovine, spinal-cord myelin. ... 

Histochemical, cytochemical, developmental, and biochemical studies indicate that much of the brain cholesterol is localized in the lipid-protein layers of the myelin sheath. As a result, this cholesterol is largely removed from the normal metabolic environment of the brain. Thus, although nervous tissue contains relatively large amounts of lipid, biosynthesis and the mean turnover rate of the typical myelin lipids including cholesterol are quite slow. Nevertheless dynamic metabolism may be found in small pools of, for example, cell or organelle membrane, cytoplasmic lipid, or outer parts of the myelin sheath. Such possibilities may serve to explain some of the various anomalous results reported by many workers studying brain cholesterol metabolism. 

Neuropathy methyl roup tranefeired to acceptor, e.0. for biosynthesis of phosphatidylcholine which is essential for myelination. Failure to produce SAM explains the neuropathy of pernicious anaemia/St2 deficient ... 

Little is known of the biosynthesis, breakdown, or role of sulfatides. Two observations seem established the biosynthesis of sulfatides coincides with the appearance of myelin and studies with the aid of a radioactive precursor have established a slow but definite turnover of sulfatides in the adult brain. Consequently, the brain constantly synthesizes and degrades sulfatides. Similar anabolic and catabolic processes are likely to occur in other tissues. 

There are many unsaturated fatty acids, characterized by having an alk-ene unit or diene or polyene units in the long carbon chain rather than the alkane chain found in 92-95. Common unsaturated fatty acids are palmitoleic acid (96 C16), oleic acid (97 C18), linolenic acid (98 C18), a-linolenic acid (99 C18), and y-linolenic acid (100 C18). Other examples include arachidonic acid (101 C20), erucic acid (102 C22— found in mustard seed), and nervonic acid (103 C24— important for the biosynthesis of nerve cell myelin). 

Fatty acids, constituents of most lipids, play a key role in membrane structure and function. Very long chain fatty acids, either saturated or mono-unsaturated are necessary to myelin therefore, their biosynthesis is fundamental for normal brain maturation. Identification of some of the biosynthetic pathways has been facilitated by the use of mutant mice (Quaking and Jimpy) characterized by a defective myelination (1) and deficient in very long chain fatty acids (2, 3). 

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