Hepatic Phosphatidylethanolamine N-Methyltransferase, Unexpected Roles in Animal Biochemistry and Physiology

Abstract

In 1961, when Bremer and Greenberg (1) characterized the methylation reactions that convert phosphatidylethanolamine (PE) 4 to phosphatidylcholine (PC), it is unlikely that they would have predicted the physiological impact of this biosynthetic conversion. Similarly, when Ridgway and Vance (2) succeeded in purification of the hepatic enzyme PE N-methyltransferase (PEMT), we considered this enzyme to be important only for making PC in the liver. Subsequent research has now clearly shown that PEMT has critical roles that are additional to the important role of supplying PC for the liver. This review will summarize research on PEMT and its impact on animal biochemistry and physiology.

The Kennedy pathway—De novo synthesis of phosphatidylethanolamine and phosphatidylcholine

“…It has been calculated that every day the mouse liver secretes into the bile the equivalent of its entire pool of PC, and with simultaneous lack of PEMT and dietary choline, PC synthesis is not able to sustain its utilization. This causes a decrease in the PC/PE ratio and an increase in membrane permeability that in turn is responsible for the development of steatohepatitis and liver failure (54,92). In addition, PEMT activity seems to be necessary for very low-density lipoprotein secretion and the regulation of the plasma supply of homocysteine, generated by the hydrolysis of the PEMT reaction byproduct S-adenosylhomocysteine.…”

“…Pem1 and Pem2 single mutants are still able to perform PE methylation: in Pem1 mutants, Pem2 could replace Pem1 to some extent; in Pem2 mutants, Pem2 activity was completely lost and led to an accumulation of GPMME, which can sufficiently replace PC in yeast. However, Pem1 Pem2 double mutants have an absolute requirement for choline in the growth media, meaning that the CDP-choline pathway has become essential (92). In mammals, a single PEMT catalyzes all three methylation reactions and is expressed mainly in the liver, where it accounts for about 30% of hepatic PC.…”

“…In mammals, a single PEMT catalyzes all three methylation reactions and is expressed mainly in the liver, where it accounts for about 30% of hepatic PC. It is an integral membrane protein with four transmembrane domains, localized in the ER and mitochondriaassociated membranes with the binding site for SAM being on the cytosolic surface (92). The significance of PE methylation in animal physiology was investigated by disrupting the Pemt gene in mice (54, 92 and references therein): even though all PEMT activity was eliminated, the Pemt null mice displayed no abnormal phenotype and normal levels of PE and PC in the liver.…”

“…In addition, PEMT activity seems to be necessary for very low-density lipoprotein secretion and the regulation of the plasma supply of homocysteine, generated by the hydrolysis of the PEMT reaction byproduct S-adenosylhomocysteine. Hyperhomocysteinemia is a risk factor for the development of cardiovascular diseases, Alzheimer disease, dementia, and bone fractures (92).…”

Nuclear export of the rate-limiting enzyme in phosphatidylcholine synthesis is mediated by its membrane binding domain

“…All mammalian cells synthesize PtdCho by the CDP-choline (Kennedy) pathway or by an alternate hepatic pathway involving sequential methylation of phosphatidylethanolamine (3). In addition to its central role in forming the limiting, semi-permeable membranes of cells and organelles, PtdCho is also a source of bioactive lipids such as phosphatidic acid, diacylglycerol (DAG) and FAs.…”