Phosphatidylethanolamine N-methyltransferase

Phosphatidylethanolamine N-methyltransferase
Identifiers
EC number 2.1.1.17
CAS number 37256-91-0
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
Overview of reactions catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT).
PEMT
Identifiers
Aliases PEMT, PEAMT, PEMPT, PEMT2, PNMT, phosphatidylethanolamine N-methyltransferase
External IDs MGI: 104535 HomoloGene: 6291 GeneCards: PEMT
Orthologs
Species Human Mouse
Entrez

10400

18618

Ensembl

ENSG00000133027

ENSMUSG00000000301

UniProt

Q9UBM1

Q61907

RefSeq (mRNA)

NM_001267551
NM_001267552
NM_007169
NM_148172
NM_148173

NM_001290011
NM_001290012
NM_001290013
NM_001290014
NM_008819

RefSeq (protein)

NP_001254480.1
NP_001254481.1
NP_009100.2
NP_680477.1
NP_680478.1

NP_001276940.1
NP_001276941.1
NP_001276942.1
NP_001276943.1
NP_032845.2

Location (UCSC) Chr 17: 17.51 – 17.59 Mb Chr 11: 59.97 – 60.05 Mb
PubMed search [1] [2]
Wikidata
View/Edit HumanView/Edit Mouse

Phosphatidylethanolamine N-methyltransferase (abbreviated PEMT) is a transferase enzyme (EC 2.1.1.17) which converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC) in the liver.[3][4][5] In humans it is encoded by the PEMT gene within the Smith-Magenis syndrome region on chromosome 17.[6][7]

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.[8][9]

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%.[8] 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.[10]

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.[5][8]

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.[11]

A major pathway for hepatic PC utilization is secretion of bile into the intestine.[5] PEMT activity also dictates normal very-low-density lipoprotein (VLDL) secretion by the liver.[12][13] PEMT is also a significant source and regulator of plasma homocysteine, which can be secreted or converted to methionine or cysteine.[14]

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.[5][15][16]

Structure

Purification of PEMT by Neale D. Ridgway and Dennis E. Vance in 1987 produced an 18.3 kDa protein.[17] Subsequent cloning, sequencing, and expression of PEMT cDNA resulted in a 22.3 kDa, 199-amino acid protein.[18] 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.[5] 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.[19]

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.[16][20][21]

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.[5][22] 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.[23]

Disease relevance

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.[8][24][25][26]

A Val-to-Met substitution at residue 175, leading to reduced PEMT activity, has been linked to non-alcoholic fatty liver disease.[27] This substitution has also been linked to increased frequency of non-alcoholic steatohepatitis.[28]

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.[29]

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.[30] PEMT deficiency prevents artherosclerosis in mice fed high-fat, high-cholesterol diets.[31] This is largely a result of lower levels of VLDL lipids in the PEMT-deficient mice.[32] 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.[5]

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.[33] 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.[34]

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.[35] Another possibility is that lack of PEMT in adipose tissue may affect normal fat deposition.[36]

See also

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. ↑ Vance DE, Li Z, Jacobs RL (Nov 2007). "Hepatic phosphatidylethanolamine N-methyltransferase, unexpected roles in animal biochemistry and physiology". The Journal of Biological Chemistry. 282 (46): 33237–41. doi:10.1074/jbc.R700028200. PMID 17881348.
  4. ↑ "EC 2.1.1.17". 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.
  5. 1 2 3 4 5 6 7 Vance DE (Mar 2013). "Physiological roles of phosphatidylethanolamine N-methyltransferase". Biochimica et Biophysica Acta. 1831 (3): 626–32. doi:10.1016/j.bbalip.2012.07.017. PMID 22877991.
  6. ↑ "Entrez Gene: PEMT".
  7. ↑ Walkey CJ, Shields DJ, Vance DE (Jan 1999). "Identification of three novel cDNAs for human phosphatidylethanolamine N-methyltransferase and localization of the human gene on chromosome 17p11.2". Biochimica et Biophysica Acta. 1436 (3): 405–12. doi:10.1016/s0005-2760(98)00147-7. PMID 9989271.
  8. 1 2 3 4 Vance DE (Jun 2014). "Phospholipid methylation in mammals: from biochemistry to physiological function". Biochimica et Biophysica Acta. 1838 (6): 1477–87. doi:10.1016/j.bbamem.2013.10.018. PMID 24184426.
  9. ↑ Jackowski S, Fagone P (Jan 2005). "CTP: Phosphocholine cytidylyltransferase: paving the way from gene to membrane". The Journal of Biological Chemistry. 280 (2): 853–6. doi:10.1074/jbc.R400031200. PMID 15536089.
  10. ↑ Christie, William W., ed. (16 September 2013). "Phosphatidylcholine and Related Lipids". AOCS Lipid Library. AOCS. Retrieved 13 February 2014.
  11. ↑ DeLong CJ, Shen YJ, Thomas MJ, Cui Z (Oct 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.
  12. ↑ Yao ZM, Vance DE (Feb 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.
  13. ↑ Vance JE, Vance DE (Aug 1985). "The role of phosphatidylcholine biosynthesis in the secretion of lipoproteins from hepatocytes". Canadian Journal of Biochemistry and Cell Biology. 63 (8): 870–81. doi:10.1139/o85-108. PMID 3904950.
  14. ↑ Refsum H, Ueland PM, Nygård O, Vollset SE (1998). "Homocysteine and cardiovascular disease". Annual Review of Medicine. 49: 31–62. doi:10.1146/annurev.med.49.1.31. PMID 9509248.
  15. ↑ Ridgway ND, Vance DE (Nov 1988). "Kinetic mechanism of phosphatidylethanolamine N-methyltransferase". The Journal of Biological Chemistry. 263 (32): 16864–71. PMID 3182819.
  16. 1 2 Ridgway ND, Yao Z, Vance DE (Jan 1989). "Phosphatidylethanolamine levels and regulation of phosphatidylethanolamine N-methyltransferase". The Journal of Biological Chemistry. 264 (2): 1203–7. PMID 2910850.
  17. ↑ Ridgway ND, Vance DE (Dec 1987). "Purification of phosphatidylethanolamine N-methyltransferase from rat liver". The Journal of Biological Chemistry. 262 (35): 17231–9. PMID 3680298.
  18. ↑ Cui Z, Vance JE, Chen MH, Voelker DR, Vance DE (Aug 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.
  19. ↑ Shields DJ, Altarejos JY, Wang X, Agellon LB, Vance DE (Sep 2003). "Molecular dissection of the S-adenosylmethionine-binding site of phosphatidylethanolamine N-methyltransferase". The Journal of Biological Chemistry. 278 (37): 35826–36. doi:10.1074/jbc.M306308200. PMID 12842883.
  20. ↑ Sundler R, Akesson B (May 1975). "Regulation of phospholipid biosynthesis in isolated rat hepatocytes. Effect of different substrates". The Journal of Biological Chemistry. 250 (9): 3359–67. PMID 1123345.
  21. ↑ Vance DE, Ridgway ND (1988). "The methylation of phosphatidylethanolamine". Progress in Lipid Research. 27 (1): 61–79. doi:10.1016/0163-7827(88)90005-7. PMID 3057511.
  22. ↑ Cole LK, Vance DE (Apr 2010). "A role for Sp1 in transcriptional regulation of phosphatidylethanolamine N-methyltransferase in liver and 3T3-L1 adipocytes". The Journal of Biological Chemistry. 285 (16): 11880–91. doi:10.1074/jbc.M110.109843. PMC 2852925Freely accessible. PMID 20150657.
  23. ↑ Resseguie ME, da Costa KA, Galanko JA, Patel M, Davis IJ, Zeisel SH (Jan 2011). "Aberrant estrogen regulation of PEMT results in choline deficiency-associated liver dysfunction". The Journal of Biological Chemistry. 286 (2): 1649–58. doi:10.1074/jbc.M110.106922. PMC 3020773Freely accessible. PMID 21059658.
  24. ↑ Walkey CJ, Yu L, Agellon LB, Vance DE (Oct 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.
  25. ↑ Smit JJ, Schinkel AH, Oude Elferink RP, Groen AK, Wagenaar E, van Deemter L, Mol CA, Ottenhoff R, van der Lugt NM, van Roon MA (Nov 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.
  26. ↑ Li Z, Agellon LB, Allen TM, Umeda M, Jewell L, Mason A, Vance DE (May 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.
  27. ↑ Song J, da Costa KA, Fischer LM, Kohlmeier M, Kwock L, Wang S, Zeisel SH (Aug 2005). "Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD)". FASEB Journal. 19 (10): 1266–71. doi:10.1096/fj.04-3580com. PMC 1256033Freely accessible. PMID 16051693.
  28. ↑ 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): 2181–2182. doi:10.1096/fj.06-1005ufm.
  29. ↑ da Costa KA, Kozyreva OG, Song J, Galanko JA, Fischer LM, Zeisel SH (Jul 2006). "Common genetic polymorphisms affect the human requirement for the nutrient choline". FASEB Journal. 20 (9): 1336–44. doi:10.1096/fj.06-5734com. PMC 1574369Freely accessible. PMID 16816108.
  30. ↑ 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.
  31. ↑ Zhao Y, Su B, Jacobs RL, Kennedy B, Francis GA, Waddington E, Brosnan JT, Vance JE, Vance DE (Sep 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.
  32. ↑ Noga AA, Zhao Y, Vance DE (Nov 2002). "An unexpected requirement for phosphatidylethanolamine N-methyltransferase in the secretion of very low density lipoproteins". The Journal of Biological Chemistry. 277 (44): 42358–65. doi:10.1074/jbc.M204542200. PMID 12193594.
  33. ↑ Jacobs RL, Zhao Y, Koonen DP, Sletten T, Su B, Lingrell S, Cao G, Peake DA, Kuo MS, Proctor SD, Kennedy BP, Dyck JR, Vance DE (Jul 2010). "Impaired de novo choline synthesis explains why phosphatidylethanolamine N-methyltransferase-deficient mice are protected from diet-induced obesity". The Journal of Biological Chemistry. 285 (29): 22403–13. doi:10.1074/jbc.M110.108514. PMC 2903412Freely accessible. PMID 20452975.
  34. ↑ 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.
  35. ↑ Wu G, Zhang L, Li T, Zuniga A, Lopaschuk GD, Li L, Jacobs RL, Vance DE (Jan 2013). "Choline supplementation promotes hepatic insulin resistance in phosphatidylethanolamine N-methyltransferase-deficient mice via increased glucagon action". The Journal of Biological Chemistry. 288 (2): 837–47. doi:10.1074/jbc.M112.415117. PMC 3543033Freely accessible. PMID 23179947.
  36. ↑ Hörl G, Wagner A, Cole LK, Malli R, Reicher H, Kotzbeck P, Köfeler H, Höfler G, Frank S, Bogner-Strauss JG, Sattler W, Vance DE, Steyrer E (May 2011). "Sequential synthesis and methylation of phosphatidylethanolamine promote lipid droplet biosynthesis and stability in tissue culture and in vivo". The Journal of Biological Chemistry. 286 (19): 17338–50. doi:10.1074/jbc.M111.234534. PMC 3089575Freely accessible. PMID 21454708.

Further reading

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