Myelin enzymes

Complete vertebrates (late Cambrian) As above plus myelinated neurons use of zinc enzymes in glial cells Free zinc in nerve messages NO/haem chemistry in glial cells ... 

Enzymes associated with myelin. Several decades ago it was generally believed that myelin was an inert membrane that did not carry out any biochemical functions. More recently, however, a large number of enzymes have been discovered in myelin [37]. These findings imply that myelin is metabolically active in synthesis, processing and metabolic turnover of some of its own components. Additionally, it may play an active role in ion transport with respect not only to maintenance of its own structure but also to participation in ion buffering near the axon. 

A few enzymes, such as the previously mentioned CNP, are believed to be fairly specific for myelin/oligodendro-cytes. There is much more in the CNS than in peripheral nerve, suggesting some function more specialized to the CNS. In addition, a unique pH 7.2 cholesterol ester hydrolase is also enriched in myelin. On the other hand, there are many enzymes that are not myelin-specific but appear to be intrinsic to myelin and not contaminants. These include cAMP-stimulated kinase, calcium/calmodulin-dependent kinase, protein kinase C, a neutral protease activity and phosphoprotein phosphatases. The protein kinase C and phosphatase activities are presumed to be responsible for the rapid turnover of MBP phosphate groups, and the PLP acylation enzyme activity is also intrinsic to myelin. 

Other enzymes present in myelin include those involved in phosphoinositide metabolism phosphatidylinositol kinase, diphosphoinositide kinase, the corresponding phosphatases and diglyceride kinases. These are of interest because of the high concentration of polyphosphoinositides of myelin and the rapid turnover of their phosphate groups. This area of research has expanded towards characterization of signal transduction system(s), with evidence of G proteins and phospholipases C and D in myelin. 

Certain enzymes shown to be present in myelin could be involved in ion transport. Carbonic anhydrase has generally been considered a soluble enzyme and a glial marker but myelin accounts for a large part of the membrane-bound form in brain. This enzyme may play a role in removal of carbonic acid from metabolically active axons. The enzymes 5 -nucleotidase and Na+, K+-ATPase have long been considered specific markers for plasma membranes and are found in myelin at low levels. The 5 -nucleotidase activity may be related to a transport mechanism for adenosine, and Na+, K+-ATPase could well be involved in transport of monovalent cations. The presence of these enzymes suggests that myelin may have an active role in ion transport in and out of the axon. In connection with this hypothesis, it is of interest that the PLP gene family may have evolved from a pore-forming polypeptide [9],... 

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.)... 

Other leukodystrophies are associated with the lysosomal and peroxisomal disorders in which specific lipids or other substances accumulate due to a deficiency in a catabolic enzyme - for example Krabbe s disease, meta-chromatic leukodystrophy (MLD) and adrenoleuko-dystrophy (ALD) [1,2]. (These are discussed in detail in Ch. 40.) Similarly, disorders of amino acid metabolism can lead to hypomyelination - for example phenylketonuria and Canavan s disease (spongy degeneration) [1, 2, 25] (Ch. 40). The composition of myelin in the genetically... 

Canavan s disease is the result of a deficiency of the enzyme that breaks down N-acetylaspartate, an important donor of acetyl groups for brain myelin synthesis 682... 

Another pathway of some importance occurs in the brain this is the cholesterol 24-hydroxylase pathway. About 25% of the body s cholesterol exists in the plasma membranes of myelin sheaths. Here, the blood-brain barrier prevents cholesterol exchanges with the circulating lipoproteins, which makes it difficult for cholesterol to leave the brain. The cytochrome P-450 enzymes (CYP 46), expressed almost exclusively in the endoplasmic reticula of the brain, allows formation of 24-hydroxycholesterol. 

Krabbe disease is caused by inherited deficiency of the lysosomal hydrolase galactocerebrosidase, the enzyme responsible for degradation of gaiactosyiceramide, a component of the myelin sheath, and other galactosphingosines (eg, psychosine). 

The enzyme was originally found to be membrane bound and resisted solubilization and purification (26). Lundblad and Moore (27), however, have reported solubilizing it using dilute (5 mM) sodium borate buffer at pH 9 after 16 hr at 37°. Studies on regional and subcellular distribution using density gradient techniques have revealed that the 2, 3 -cyclic phosphate diesterase concentrates in those fractions containing myelin (28, 29), and the conclusion has been reached that the enzyme is localized in the myelin sheath or intimately associated structures. Kurihara and... 

Tsukada (30) have examined developmental changes of the enzyme in chick brain and spinal cord. Enzymic activity appears at about the eighteenth day of incubation and increases rapidly until 3 days after hatching in the brain and between 18 and 21 days of incubation in the spinal cord. These are precisely the periods of active myelination in the brain and spinal cord of the chick, respectively. Similarly, brain tissue of the newborn rat is devoid of cyclic phosphate diesterase activity it appears at about 8 days after birth and increases dramatically between the tenth and thirty-fifth day of life (29). This coincides precisely with the development of myelin in this species. The diesterase is essentially absent in the brain of the jimpy mouse (31), a lethal mutant devoid of myelin in the central nervous system. It is also absent from the spinal cord of this mutant. The enzyme is about 50% deficient in brain tissue of the quaking mouse (29), a mutant with partial deficiency of myelin. There is no activity in nerve fibers and ganglia from a variety of invertebrates such as squid, octopus, crab, shrimp, and starfish. Nerve tissue in these organisms is nonmyelinated. All these observations point to an intimate association of the enzyme with myelin in vivo. 

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