Phosphatidylethanolamine N-methyltransferase
Phosphatidylethanolamine N-methyltransferase (abbreviated PEMT) is a transferase enzyme (EC 2.1.1.17) which converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC) in the liver.[5][6][7] In humans it is encoded by the PEMT gene within the Smith–Magenis syndrome region on chromosome 17.[8][9]
Phosphatidylethanolamine N-methyltransferase
While the CDP-choline pathway, in which choline obtained either by dietary consumption or by metabolism of choline-containing lipids is converted to PC, accounts for approximately 70% of PC biosynthesis in the liver, the PEMT pathway has been shown to have played a critical evolutionary role in providing PC during times of starvation. Furthermore, PC made via PEMT plays a wide range of physiological roles, utilized in choline synthesis, hepatocyte membrane structure, bile secretion, and very low-density lipoprotein (VLDL) secretion.[10][11]
Nomenclature[edit]
Phosphatidylethanolamine N-methyltransferase is also known as lipid methyl transferase, LMTase, phosphatidylethanolamine methyltransferase, phosphatidylethanolamine-N-methylase, and phosphatidylethanolamine-S-adenosylmethionine-methyltransferase.
Function[edit]
The PEMT enzyme converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC) via three sequential methylations by S-adenosyl methionine (SAM). The enzyme is found in endoplasmic reticulum and mitochondria-associated membranes. It accounts for ~30% of PC biosynthesis, with the CDP-choline, or Kennedy, pathway making ~70%.[10] PC, typically the most abundant phospholipid in animals and plants, accounts for more than half of cell membrane phospholipids and approximately 30% of all cellular lipid content. The PEMT pathway is therefore crucial for maintaining membrane integrity.[12]
PC made via the PEMT pathway can be degraded by phospholipases C/D, resulting in the de novo formation of choline. Thus, the PEMT pathway contributes to maintaining brain and liver function and larger-scale energy metabolism in the body.[7][10]
PC molecules produced by PEMT-catalyzed methylation of PE are more diverse, and tend to contain longer chain, polyunsaturated species and more arachidonate, whereas those produced via the CDP-choline pathway are typically composed of medium-length, saturated chains.[13]
A major pathway for hepatic PC utilization is secretion of bile into the intestine.[7] PEMT activity also dictates normal very low-density lipoprotein (VLDL) secretion by the liver.[14][15] PEMT is also a significant source and regulator of plasma homocysteine, which can be secreted or converted to methionine or cysteine.[16]
Mechanism[edit]
The exact mechanism by which PEMT catalyzes the sequential methylation of PE by three molecules of SAM to form PC remains unknown. Kinetic analyses as well as amino acid and gene sequencing have shed some light on how the enzyme works. Studies suggest that a single substrate binding site binds all three phospholipids methylated by PEMT: PE, phosphatidyl-monomethylethanolamine (PMME) and phosphatidyl-dimethylethanolamine. The first methylation, that of PE to PMME, has been shown to be the rate-limiting step in conversion of PE to PC. It is suspected that the structure or specific conformation adopted by PE has a lower affinity for the PEMT active site; consequently, upon methylation, PMME would be immediately converted to PDME and PDME to PC, via a Bi-Bi or ping-pong mechanism before another PE molecule could enter the active site.[7][17][18]
Structure[edit]
Purification of PEMT by Neale D. Ridgway and Dennis E. Vance in 1987 produced an 18.3 kDa protein.[19] Subsequent cloning, sequencing, and expression of PEMT cDNA resulted in a 22.3 kDa, 199-amino acid protein.[20] Although the enzymatic structure is unknown, PEMT is proposed to contain four hydrophobic membrane-spanning regions, with both its C and N termini on the cytosolic side of the ER membrane. Kinetic studies indicate a common binding site for PE, PMME, and PDME substrates.[7] SAM binding motifs have been identified on both the third and fourth transmembrane sequences. Site-directed mutagenesis has pinpointed the residues Gly98, Gly100, Glu180, and Glu181 to be essential for SAM binding in the active site.[21]
Regulation[edit]
PEMT activity is unrelated to enzyme mass, but rather is regulated by supply of substrates including PE, as well as PMME, PDME, and SAM. Low substrate levels inhibit PEMT. The enzyme is further regulated by S-adenosylhomocysteine produced after each methylation.[18][22][23]
PEMT gene expression is regulated by transcription factors including activator protein 1 (AP-1) and Sp1. Sp1 is a negative regulator of PEMT transcription, yet is it is a positive regulator of choline-phosphate cytidylyltransferase (CT) transcription.[7][24] This is one of several examples of the reciprocal regulation of PEMT and CT in the PEMT and CDP-choline pathways. Estrogen has also been shown to be a positive regulator of hepatocyte PEMT transcription. Ablation of the estrogen binding site in the PEMT promoter region may increase risk of hepatic steatosis from choline deficiency.[25]
This article incorporates text from the United States National Library of Medicine, which is in the public domain.