Phosphatidylethanolamine N-methyltransferase

Phosphatidylethanolamine N-methyltransferase
Identifiers
EC number	2.1.1.17
CAS number	Template:CAS
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search PMC articles PubMed articles NCBI proteins

File:PEMT Enzyme-Catalyzed Reaction.png

Overview of reactions catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT).

Phosphatidylethanolamine N-methyltransferase (abbreviated PEMT) is a transferase enzyme (EC 2.1.1.17) which converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC) in the liver. In humans it is encoded by the PEMT gene within the Smith-Magenis syndrome region on chromosome 17.

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.

Nomenclature

Phosphatidylethanolamine N-methyltransferase is also known as lipid methyl transferase, LMTase, phosphatidylethanolamine methyltransferase, phosphatidylethanolamine-N-methylase, and phosphatidylethanolamine-S-adenosylmethionine-methyltransferase.

Function

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%. 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.

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.

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.

A major pathway for hepatic PC utilization is secretion of bile into the intestine. PEMT activity also dictates normal very-low-density lipoprotein (VLDL) secretion by the liver. PEMT is also a significant source and regulator of plasma homocysteine, which can be secreted or converted to methionine or cysteine.

Mechanism

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.

Structure

Purification of PEMT by Neale D. Ridgway and Dennis E. Vance in 1987 produced an 18.3 kDa protein. Subsequent cloning, sequencing, and expression of PEMT cDNA resulted in a 22.3 kDa, 199-amino acid protein. 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. 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.

Regulation

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.

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. 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.

Disease relevance

File:PEMT Roles and Regulation.jpg

Overview of biological roles and regulation of phosphatidylethanolamine N-methyltransferase (PEMT)

Liver

PEMT deficiency in mice, genetically induced by PEMT gene knockout, produced minimal effect on PE and PC levels. However, upon being fed a choline-deficient diet, the mice developed severe liver failure. Rapid PC depletion due to biliary PC secretion, as well as protein leakage from loss of membrane integrity due to lowered PC/PE ratios, led to steatosis and steatohepatitis.

A Val-to-Met substitution at residue 175, leading to reduced PEMT activity, has been linked to non-alcoholic fatty liver disease. This substitution has also been linked to increased frequency of non-alcoholic steatohepatitis.

A single-nucleotide polymorphism (G to C) in the promoter region of the PEMT has been demonstrated to contribute to development of organ dysfunction in conjunction with a low-choline diet.

Cardiovascular disease and artherosclerosis

PEMT modulates levels of blood plasma homocysteine, which is either secreted or converted to methionine or cysteine. High levels of homocysteine are linked to cardiovascular disease and artherosclerosis, particularly coronary artery disease. PEMT deficiency prevents artherosclerosis in mice fed high-fat, high-cholesterol diets. This is largely a result of lower levels of VLDL lipids in the PEMT-deficient mice. Furthermore, the decreased lipid (PC) content in VLDLs causes changes in lipoprotein structure which allow them to be cleared more rapidly in the PEMT-deficient mice.

Obesity and insulin resistance

PEMT-deficient mice fed high-fat diets have been shown to resist weight gain and be protected from insulin resistance. One potential reason for this phenomenon is that these mice, which exhibit hypermetabolic behavior, rely more on glucose than on fats for energy. It was concluded that insufficient choline resulted in the lack of weight gain, supported by the fact that PC produced via the PEMT pathway can be used to form choline.

The PEMT deficient mice showed elevated plasma glucagon levels, increased hepatic expression of glucagon receptor, phosphorylated AMP-activated protein kinase (AMPK), and serine-307-phosphorylated insulin receptor substrate 1 (IRS1-s307), which blocks insulin-mediated signal transduction; together, these contribute to enhanced gluconeogenesis and ultimately insulin resistance. Another possibility is that lack of PEMT in adipose tissue may affect normal fat deposition.

See also

• Phosphatidylethanolamine

External links

• Phosphatidylethanolamine N-Methyltransferase at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.