In:
Biochemistry and Cell Biology, Canadian Science Publishing, Vol. 68, No. 10 ( 1990-10-01), p. 1151-1165
Abstract:
Phosphatidylcholine is apparently essential for mammalian life, since there are no known inherited diseases in the biosynthesis of this lipid. One of its critical roles appears to be in the structure of the eucaryotic membranes. Why phosphatidylcholine is required and why other phospholipids will not substitute are unknown. The major pathway for the biosynthesis of phosphatidylcholine occurs via the CDP-choline pathway. Choline kinase, the initial enzyme in the sequence, has been purified to homogeneity from kidney and liver and also catalyzes the phosphorylation of ethanolamine. Most evidence suggests that the next enzyme in the pathway, CTP:phosphocholine cytidylyltransferase, catalyzes the rate-limiting and regulated step in phosphatidylcholine biosynthesis. This enzyme has also been completely purified from liver. Cytidylyltransferase appears to exist in the cytosol as an inactive reservoir of enzyme and as a membrane-bound form (largely associated with the endoplasmic reticulum), which is activated by the phospholipid environment. There is evidence that the activity of this enzyme and the rate of phosphatidylcholine biosynthesis are regulated by the reversible translocation of the cytidylyltransferase between membranes and cytosol. Three major mechanisms appear to govern the distribution and cellular activity of this enzyme. (i) The enzyme is phosphorylated by cAMP-dependent protein kinase, which results in release of the enzyme into the cytosol. Reactivation of cytidylyltransferase by binding to membranes can occur by the action of protein phosphatase 1 or 2A. (ii) Fatty acids added to cells in culture or in vitro causes the enzyme to bind to membranes where it is activated. Removal of the fatty acids dissociates the enzyme from the membrane, (iii) Perhaps most importandy, the concentration of phosphatidylcholine in the endoplasmic reticulum feedback regulates the distribution of cytidylyltransferase. A decrease in the level of phosphatidylcholine causes the enzyme to be activated by binding to the membrane, whereas an increase in phosphatidylcholine mediates the release of enzyme into the cytosol. The third enzyme in the CDP-choline pathway, CDP-choline: 1,2-diacylglycerol cholinephosphotransferase, has been cloned from yeast but never purified from any source. In liver an alternative pathway for phosphatidylcholine biosynthesis is the methylation of phosphatidylethanolamine by phosphatidylethanolamine N-methyltransferase. This enzyme is membrane bound and has been purified to homogeneity. It catalyzes all three methylation reactions involved in the conversion of phosphatidylethanolamine to phosphatidylcholine. The activity of this enzyme is 100- to 1000-fold lower in other cells and tissues derived from animals. In yeast there are two phospholipid methyltransferases involved in the methylation of phosphatidylethanolamine. The genes encoding both of these enzymes have been cloned and the primary structure of the enzymes have been deduced. Phosphatidylcholine is also catabolized in liver. Only one enzyme involved in this process has been purified to homogeneity, that is, phospholipase A 2 from mitochondria. The mechanisms involved in the regulation of phosphatidylcholine catabolism are largely unknown. Phosphatidylcholine is a major component of plasma lipoproteins and the active synthesis of phosphatidylcholine is required for the secretion of very low density lipoproteins from liver. In contrast, the secretion of high density lipoproteins, albumin, and all other secreted proteins do not require the active biosynthesis of phosphatidylcholine. Other phospholipids will not substitute for the phosphatidylcholine requirement. It is also apparent that newly made phosphatidylcholine, rather than preexisting phosphatidylcholine, is preferentially utilized for lipoprotein secretion.Key words: phosphatidylcholine, glycerophosphocholine, cytidylyltransferase, methyltransferase, cholinephosphotransferase.
Type of Medium:
Online Resource
ISSN:
0829-8211
,
1208-6002
Language:
English
Publisher:
Canadian Science Publishing
Publication Date:
1990
SSG:
12
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