P. Pritchard, P. Chiang, G. Cantoni
Jun 10, 1982
Citations
1
Influential Citations
73
Citations
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Journal
The Journal of biological chemistry
Abstract
The effect of 3-deazaadenosine on phosphatidylcholine biosynthesis has been studied in rat liver in vivo and in adult rat hepatocytes maintained in monolayer culture. The drug had a marked inhibitory effect on phosphatidylcholine biosynthesis via the N-methylation of phosphatidylethanolamine. In contrast, treatment of rats or hepatocytes with 3-deazaadenosine caused a 2- to %fold increase in phosphatidylcholine biosynthesis via CDP-choline. The effect of the drug was much less marked on phosphatidylcholine biosynthesis in rat spleen, and no significant effect was observed in rat brain. Experiments indicated that the reaction catalyzed by CTP:phosphocholine cytidylyltransferase was stimulated approximately %fold by treatment of the hepatocytes with 3-deazaadenosine and this could account for the increased rate of phosphatidylcholine biosynthesis. This enzyme activation appeared to be associated with a redistribution of enzyme protein from the cytosol to the microsomes. No effect was observed on the activity of microsomal phosphatidylethanolamine-N-methyltransferase. However, a metabolite of 3-deazaadenosine, S-3-deazasdenosylL-homocysteine, was shown to be a competitive inhibitor of the N-methyltransferase with respect to S-adenosyl-L-methionine. The results suggest that treatment with 3-deazaadenosine causes an inhibition of phosphatidylethanolamine-N-methylation by the accumulation of two competitive inhibitors, S-adenosylL-homocysteine and S-3-deazaadenosyl-~-homocysteine. There appears to be cookdinate regulation of phosphatidylcholine biosynthesis via CDP-choline and N-methylation of phosphatidylethanolamine. However, the mechanism by which 3-deazaadenosine causes a stimulation and redistribution of the cytidylyltransferase reaction remains to be elucidated.