Phosphatidylethanolamine N-methyltransferase

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Phosphatidylethanolamine N-methyltransferase
EC number
CAS number 37256-91-0
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Overview of reactions catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT).

Phosphatidylethanolamine N-methyltransferase (abbreviated PEMT, also lipid methyl transferase, LMTase, phosphatidylethanolamine methyltransferase, phosphatidylethanolamine-N-methylase, phosphatidylethanolamine-S-adenosylmethionine methyltransferase) is an enzyme (EC of the transferase class which catalyzes the conversion of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) in the liver via three sequential methylations by S-adenosyl methionine (SAM).[1][2]

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.[3][4]

Biological function[edit]

The PEMT enzyme, which is found in endoplasmic reticulum (ER) membranes and is only highly expressed in the liver, catalyzes all three transmethylations in the conversion of phosphatidylethanolamine (PE) to phosphatidylcholine (PC). The PEMT pathway accounts for approximately 30% of PC biosynthesis, with the CDP-choline, or Kennedy, pathway accounting for the majority (approximately 70%).[3] 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. Proper functioning of the PEMT pathway is therefore crucial for maintaining membrane integrity.[5]

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 liver function and larger-scale energy metabolism in the body.[2][3]

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.[6]

A major pathway for hepatic PC utilization is secretion of bile into the intestine.[2] PEMT activity also dictates normal very-low-density lipoprotein (VLDL) secretion by the liver.[7][8] PEMT is also a significant source and regulator of plasma homocysteine, which can be secreted or converted to methionine or cysteine.[9]

Enzyme 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.[2][10][11]

Enzyme structure[edit]

Purification of PEMT by Neale D. Ridgway and Dennis E. Vance in 1987 produced an 18.3 kDa protein.[12] Subsequent cloning, sequencing, and expression of PEMT cDNA resulted in a 22.3 kDa, 199-amino acid protein.[13] 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.[2] 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.[14]

Enzyme 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.[11][15][16]

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.[2][17] 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.[18]

Disease relevance[edit]

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


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.[3][19][20][21]

A Val-to-Met substitution at residue 175, leading to reduced PEMT activity, has been linked to non-alcoholic fatty liver disease.[22] This substitution has also been linked to increased frequency of non-alcoholic steatohepatitis.[23]

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.[24]

Cardiovascular disease and artherosclerosis[edit]

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.[25] PEMT deficiency prevents artherosclerosis in mice fed high-fat, high-cholesterol diets.[26] This is largely a result of lower levels of VLDL lipids in the PEMT-deficient mice.[27] 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.[2]

Obesity and insulin resistance[edit]

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.[28] 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.[29]

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.[30] Another possibility is that lack of PEMT in adipose tissue may affect normal fat deposition.[31]

See also[edit]


  1. ^ "EC". International Union of Biochemistry and Molecular Biology Nomenclature. School of Biological and Chemical Sciences, Queen Mary, University of London. 17 February 2014. Retrieved 25 February 2014. 
  2. ^ a b c d e f g Vance, D. E. (2013). "Physiological roles of phosphatidylethanolamine N-methyltransferase". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1831 (3): 626–32. doi:10.1016/j.bbalip.2012.07.017. PMID 22877991.  edit
  3. ^ a b c d Vance, D. E. (2013). "Phospholipid methylation in mammals: From biochemistry to physiological function". Biochimica et Biophysica Acta (BBA) - Biomembranes 1838 (6): 1477–87. doi:10.1016/j.bbamem.2013.10.018. PMID 24184426.  edit
  4. ^ Jackowski, S; Fagone, P (2005). "CTP: Phosphocholine cytidylyltransferase: Paving the way from gene to membrane". Journal of Biological Chemistry 280 (2): 853–6. doi:10.1074/jbc.R400031200. PMID 15536089.  edit
  5. ^ Christie, William W., ed. (16 September 2013). "Phosphatidylcholine and Related Lipids". AOCS Lipid Library. AOCS. Retrieved 13 February 2014. 
  6. ^ Delong, C. J.; Shen, Y. J.; Thomas, M. J.; Cui, Z (1999). "Molecular distinction of phosphatidylcholine synthesis between the CDP-choline pathway and phosphatidylethanolamine methylation pathway". The Journal of Biological Chemistry 274 (42): 29683–8. doi:10.1074/jbc.274.42.29683. PMID 10514439.  edit
  7. ^ Yao, Z. M.; Vance, D. E. (1988). "The active synthesis of phosphatidylcholine is required for very low density lipoprotein secretion from rat hepatocytes". The Journal of Biological Chemistry 263 (6): 2998–3004. PMID 3343237.  edit
  8. ^ Vance, J. E.; Vance, D. E. (1985). "The role of phosphatidylcholine biosynthesis in the secretion of lipoproteins from hepatocytes". Biochemistry and Cell Biology 63 (8): 870–81. doi:10.1139/o85-108. PMID 3904950.  edit
  9. ^ Refsum, H; Ueland, P. M.; Nygård, O; Vollset, S. E. (1998). "Homocysteine and cardiovascular disease". Annual Review of Medicine 49: 31–62. doi:10.1146/ PMID 9509248.  edit
  10. ^ Ridgway, N. D.; Vance, D. E. (1988). "Kinetic mechanism of phosphatidylethanolamine N-methyltransferase". The Journal of Biological Chemistry 263 (32): 16864–71. PMID 3182819.  edit
  11. ^ a b Ridgway, N. D.; Yao, Z; Vance, D. E. (1989). "Phosphatidylethanolamine levels and regulation of phosphatidylethanolamine N-methyltransferase". The Journal of Biological Chemistry 264 (2): 1203–7. PMID 2910850.  edit
  12. ^ Ridgway, N. D.; Vance, D. E. (1987). "Purification of phosphatidylethanolamine N-methyltransferase from rat liver". The Journal of Biological Chemistry 262 (35): 17231–9. PMID 3680298.  edit
  13. ^ Cui, Z; Vance, J. E.; Chen, M. H.; Voelker, D. R.; Vance, D. E. (1993). "Cloning and expression of a novel phosphatidylethanolamine N-methyltransferase. A specific biochemical and cytological marker for a unique membrane fraction in rat liver". The Journal of Biological Chemistry 268 (22): 16655–63. PMID 8344945.  edit
  14. ^ Shields, D. J.; Altarejos, J. Y.; Wang, X; Agellon, L. B.; Vance, D. E. (2003). "Molecular dissection of the S-adenosylmethionine-binding site of phosphatidylethanolamine N-methyltransferase". Journal of Biological Chemistry 278 (37): 35826–36. doi:10.1074/jbc.M306308200. PMID 12842883.  edit
  15. ^ Sundler, R; Akesson, B (1975). "Regulation of phospholipid biosynthesis in isolated rat hepatocytes. Effect of different substrates". The Journal of Biological Chemistry 250 (9): 3359–67. PMID 1123345.  edit
  16. ^ Vance, D. E.; Ridgway, N. D. (1988). "The methylation of phosphatidylethanolamine". Progress in Lipid Research 27 (1): 61–79. PMID 3057511.  edit
  17. ^ Cole, L. K.; Vance, D. E. (2010). "A role for Sp1 in transcriptional regulation of phosphatidylethanolamine N-methyltransferase in liver and 3T3-L1 adipocytes". Journal of Biological Chemistry 285 (16): 11880–91. doi:10.1074/jbc.M110.109843. PMC 2852925. PMID 20150657.  edit
  18. ^ Resseguie, M. E.; Da Costa, K. A.; Galanko, J. A.; Patel, M; Davis, I. J.; Zeisel, S. H. (2011). "Aberrant estrogen regulation of PEMT results in choline deficiency-associated liver dysfunction". Journal of Biological Chemistry 286 (2): 1649–58. doi:10.1074/jbc.M110.106922. PMC 3020773. PMID 21059658.  edit
  19. ^ Walkey, C. J.; Yu, L; Agellon, L. B.; Vance, D. E. (1998). "Biochemical and evolutionary significance of phospholipid methylation". The Journal of Biological Chemistry 273 (42): 27043–6. doi:10.1074/jbc.273.42.27043. PMID 9765216.  edit
  20. ^ Smit, J. J.; Schinkel, A. H.; Oude Elferink, R. P.; Groen, A. K.; Wagenaar, E; Van Deemter, L; Mol, C. A.; Ottenhoff, R; Van Der Lugt, N. M.; Van Roon, M. A. (1993). "Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease". Cell 75 (3): 451–62. doi:10.1016/0092-8674(93)90380-9. PMID 8106172.  edit
  21. ^ Li, Z; Agellon, L. B.; Allen, T. M.; Umeda, M; Jewell, L; Mason, A; Vance, D. E. (2006). "The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis". Cell Metabolism 3 (5): 321–31. doi:10.1016/j.cmet.2006.03.007. PMID 16679290.  edit
  22. ^ Song, J; Da Costa, K. A.; Fischer, L. M.; Kohlmeier, M; Kwock, L; Wang, S; Zeisel, S. H. (2005). "Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD)". The FASEB Journal 19 (10): 1266–71. doi:10.1096/fj.04-3580com. PMC 1256033. PMID 16051693.  edit
  23. ^ Zeisel, S. H. (2006). "People with fatty liver are more likely to have the PEMT rs7946 SNP, yet populations with the mutant allele do not have fatty liver". The FASEB Journal 20 (12): 2181. doi:10.1096/fj.06-1005ufm.  edit
  24. ^ Da Costa, K. A.; Kozyreva, O. G.; Song, J; Galanko, J. A.; Fischer, L. M.; Zeisel, S. H. (2006). "Common genetic polymorphisms affect the human requirement for the nutrient choline". The FASEB Journal 20 (9): 1336–44. doi:10.1096/fj.06-5734com. PMC 1574369. PMID 16816108.  edit
  25. ^ Robinson, Killian H. (2001). "Homocysteine and coronary artery disease". In Carmel, Ralph; Jacobsen, Ralph Carmel. Homocysteine in Health and Disease. Cambridge: Cambridge University Press. pp. 371–383. 
  26. ^ Zhao, Y; Su, B; Jacobs, R. L.; Kennedy, B; Francis, G. A.; Waddington, E; Brosnan, J. T.; Vance, J. E.; Vance, D. E. (2009). "Lack of phosphatidylethanolamine N-methyltransferase alters plasma VLDL phospholipids and attenuates atherosclerosis in mice". Arteriosclerosis, Thrombosis, and Vascular Biology 29 (9): 1349–55. doi:10.1161/ATVBAHA.109.188672. PMID 19520976.  edit
  27. ^ Noga, A. A.; Zhao, Y; Vance, D. E. (2002). "An unexpected requirement for phosphatidylethanolamine N-methyltransferase in the secretion of very low density lipoproteins". Journal of Biological Chemistry 277 (44): 42358–65. doi:10.1074/jbc.M204542200. PMID 12193594.  edit
  28. ^ Jacobs, R. L.; Zhao, Y; Koonen, D. P.; Sletten, T; Su, B; Lingrell, S; Cao, G; Peake, D. A.; Kuo, M. S.; Proctor, S. D.; Kennedy, B. P.; Dyck, J. R.; Vance, D. E. (2010). "Impaired de novo choline synthesis explains why phosphatidylethanolamine N-methyltransferase-deficient mice are protected from diet-induced obesity". Journal of Biological Chemistry 285 (29): 22403–13. doi:10.1074/jbc.M110.108514. PMC 2903412. PMID 20452975.  edit
  29. ^ Zeisel, Steven H. (1987). "Phosphatidylcholine: Endogenous Precursor of Choline". In Hanin, Israel; Ansell, Gordon Brian. Lecithin: Technological, Biological and Therapeutic Aspects. New York: Plenum Press. pp. 107–120. 
  30. ^ Wu, G; Zhang, L; Li, T; Zuniga, A; Lopaschuk, G. D.; Li, L; Jacobs, R. L.; Vance, D. E. (2013). "Choline supplementation promotes hepatic insulin resistance in phosphatidylethanolamine N-methyltransferase-deficient mice via increased glucagon action". Journal of Biological Chemistry 288 (2): 837–47. doi:10.1074/jbc.M112.415117. PMC 3543033. PMID 23179947.  edit
  31. ^ Hörl, G; Wagner, A; Cole, L. K.; Malli, R; Reicher, H; Kotzbeck, P; Köfeler, H; Höfler, G; Frank, S; Bogner-Strauss, J. G.; Sattler, W; Vance, D. E.; Steyrer, E (2011). "Sequential synthesis and methylation of phosphatidylethanolamine promote lipid droplet biosynthesis and stability in tissue culture and in vivo". Journal of Biological Chemistry 286 (19): 17338–50. doi:10.1074/jbc.M111.234534. PMC 3089575. PMID 21454708.  edit

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