Locations and contributions of the phosphotransferases EPT1 and CEPT1 to the biosynthesis of ethanolamine phospholipids

Abstract

The final step of the CDP-ethanolamine pathway is catalyzed by ethanolamine phosphotransferase 1 (EPT1) and choline/EPT1 (CEPT1). These enzymes are likely involved in the transfer of ethanolamine phosphate from CDP-ethanolamine to lipid acceptors such as 1,2-diacylglycerol (DAG) for PE production and 1-alkyl-2-acyl-glycerol (AAG) for the generation of 1-alkyl-2-acyl-glycerophosphoethanolamine. Here, we investigated the intracellular location and contribution to ethanolamine phospholipid (EP) biosynthesis of EPT1 and CEPT1 in HEK293 cells. Immunohistochemical analyses revealed that EPT1 localizes to the Golgi apparatus and CEPT1 to the ER. We created EPT1-, CEPT1-, and EPTI-CEPT1-deficient cells, and labeling of these cells with radio- or deuterium-labeled ethanolamine disclosed that EPT1 is more important for the de novo biosynthesis of 1-alkenyl-2-acyl-glycerophosphoethanolamine than is CEPT1. EPT1 also contributed to the synthesis of PE species containing the fatty acids 36:1, 36:4, 38:5, 38:4, 38:3, 40:6, 40:5, and 40:4. In contrast, CEPT1 was important for PE formation from shorter fatty acids such as 32:2, 32:1, 34:2, and 34:1. Brefeldin A treatment did not significantly affect the levels of the different PE species, indicating that the subcellular localization of the two enzymes is not responsible for their substrate preferences. In vitro enzymatic analysis revealed that EPT1 prefers AAG 16–20:4 > DAG 18:0–20:4 > DAG 16:0–18:1 = AAG 16–18:1 as lipid acceptors and that CEPT1 greatly prefers DAG 16:0–18:1 to other acceptors. These results suggest that EPT1 and CEPT1 differ in organelle location and are responsible for the biosynthesis of distinct EP species. The final step of the CDP-ethanolamine pathway is catalyzed by ethanolamine phosphotransferase 1 (EPT1) and choline/EPT1 (CEPT1). These enzymes are likely involved in the transfer of ethanolamine phosphate from CDP-ethanolamine to lipid acceptors such as 1,2-diacylglycerol (DAG) for PE production and 1-alkyl-2-acyl-glycerol (AAG) for the generation of 1-alkyl-2-acyl-glycerophosphoethanolamine. Here, we investigated the intracellular location and contribution to ethanolamine phospholipid (EP) biosynthesis of EPT1 and CEPT1 in HEK293 cells. Immunohistochemical analyses revealed that EPT1 localizes to the Golgi apparatus and CEPT1 to the ER. We created EPT1-, CEPT1-, and EPTI-CEPT1-deficient cells, and labeling of these cells with radio- or deuterium-labeled ethanolamine disclosed that EPT1 is more important for the de novo biosynthesis of 1-alkenyl-2-acyl-glycerophosphoethanolamine than is CEPT1. EPT1 also contributed to the synthesis of PE species containing the fatty acids 36:1, 36:4, 38:5, 38:4, 38:3, 40:6, 40:5, and 40:4. In contrast, CEPT1 was important for PE formation from shorter fatty acids such as 32:2, 32:1, 34:2, and 34:1. Brefeldin A treatment did not significantly affect the levels of the different PE species, indicating that the subcellular localization of the two enzymes is not responsible for their substrate preferences. In vitro enzymatic analysis revealed that EPT1 prefers AAG 16–20:4 > DAG 18:0–20:4 > DAG 16:0–18:1 = AAG 16–18:1 as lipid acceptors and that CEPT1 greatly prefers DAG 16:0–18:1 to other acceptors. These results suggest that EPT1 and CEPT1 differ in organelle location and are responsible for the biosynthesis of distinct EP species. Ethanolamine phospholipid (EP) in mammalian cells mainly comprises PE. In many cells and tissues, PE is the second most abundant phospholipid after PC and generally constitutes approximately 20–40% of cellular phospholipids (1Vance J.E. Phospholipid synthesis and transport in mammalian cells.Traffic. 2015; 16: 1-18Crossref PubMed Scopus (241) Google Scholar). PE is composed of DAG and ethanolamine phosphate. Another type of EP found in mammalian cells is ether-linked lipid such as 1-alkyl-2-acyl-glycerophosphoethanolamine (plasmanyl-PE) and 1-alkenyl-2-acyl-glycerophosphoethanolamine (plasmenyl-PE), also called plasmalogen. Lipid moieties of these EPs are 1-alkyl-2-acyl-glycerol (AAG) and 1-alkenyl-2-acyl-glycerol, respectively. In mammals, 20% of total phospholipids have ether-linkage, but quantity of the lipid varies from tissue to tissue. In human brain, plasmenyl-PE is the main EP (up to 80% of total EP). The lipid is also found in heart, lung, kidney, spleen, skeletal muscle, and testis. Liver contains plasmenyl-PE as less than 1% of the total phospholipids. Generally, the 1-alkenyl group is present in plasmenyl-PE, whereas the 1-alkyl group is present in 1-alkyl-2-acyl-glycerophosphocholine (plasmanyl-PC). The content of plasmanyl-PC is highest in heart and skeletal muscle and is low in other organs. Figure 1 shows the biosynthetic pathway and subcellular location for synthesis of PE, plasmanyl-PE, and plasmenyl-PE in mammalian cells. PE is mainly synthesized by two pathways: the PS decarboxylation pathway and the CDP-ethanolamine pathway (or Kennedy pathway) (Fig. 1A) (2Vance J.E. Historical perspective: phosphatidylserine and phosphatidylethanolamine from the 1800s to the present.J. Lipid Res. 2018; 59: 923-944Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). In the PS decarboxylation pathway, the serine base in PS is decarboxylated by PS decarboxylase (PSD) to generate PE on the mitochondrial inner membrane. The PS decarboxylation pathway and the CDP-ethanolamine pathway generate different PE molecular species. In McA-RH7777 and Chinese hamster ovary K1 (CHO-K1) cells, the PS decarboxylation pathway is involved in the synthesis of PE molecular species mainly containing polyunsaturated fatty acids such as 18:0–20:4, 18:0–20:5, and 18:0–22:6. In contrast, the CDP-ethanolamine pathway preferentially synthesizes PE molecular species such as 16:0–18:2 and 18:1–18:2 (3Bleijerveld O.B. Brouwers J.F. Vaandrager A.B. Helms J.B. Houweling M. The CDP-ethanolamine pathway and phosphatidylserine decarboxylation generate different phosphatidylethanolamine molecular species.J. Biol. Chem. 2007; 282: 28362-28372Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). The first step in the CDP-ethanolamine pathway is the phosphorylation of ethanolamine by ethanolamine kinase to produce ethanolamine phosphate. The second step is catalyzed by CTP:phosphoethanolamine cytidylyltransferase (ET) encoded by PCYT2, which activates ethanolamine phosphate by interaction with CDP to produce CDP-ethanolamine. PE is finally synthesized by transferring phosphoethanolamine from CDP-ethanolamine to DAG, with the release of CMP by ethanolamine phosphotransferase. Two different ethanolamine phosphotransferases, such as choline/ethanolamine phosphotransferase 1 (CEPT1) (4Henneberry A.L. McMaster C.R. Cloning and expression of a human choline/ethanolaminephosphotransferase: synthesis of phosphatidylcholine and phosphatidylethanolamine.Biochem. J. 1999; 339: 291-298Crossref PubMed Scopus (85) Google Scholar) and ethanolamine phosphotransferase 1 (EPT1) (5Horibata Y. Hirabayashi Y. Identification and characterization of human ethanolaminephosphotransferase1.J. Lipid Res. 2007; 48: 503-508Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar), are involved in this final step. The biosynthesis of ether-linked PE requires peroxisomes, in which 1-alkyl-dihydroxyacetone phosphate (DHAP) is synthesized by DHAP acyltransferase and alkyl-DHAP synthase (Fig. 1B). After reduction of 1-alkyl-DHAP to produce 1-alkyl-glycerol-3-phosphate (G3P) in peroxisomes, the intermediate is transferred to the ER and acylated to generate 1-alkyl-2-acyl-G3P, which is then dephosphorylated to produce AAG. For the synthesis of plasmenyl-PE, plasmanyl-PE is first synthesized from CDP-ethanolamine and AAG by ethanolamine phosphotransferase, then the 1-alkyl group in plasmanyl-PE is desaturated to the 1-alkenyl group by plasmanyl-PE desaturase (PEDS), producing plasmenyl-PE (6Wykle R.L. Blank M.L. Malone B. Snyder F. Evidence for a mixed function oxidase in the biosynthesis of ethanolamine plasmalogens from 1-alkyl-2-acyl-sn-glycero-3-phosphorylethanolamine.J. Biol. Chem. 1972; 247: 5442-5447Abstract Full Text PDF PubMed Google Scholar). The TMEM189 gene was recently identified as encoding PEDS (7Gallego-García A. Monera-Girona A.J. Pajares-Martinez E. Bastida-Martinez E. Perez-Castano R. Iniesta A.A. Fontes M. Padmanabhan S. Elias-Arnanz M. A bacterial light response reveals an orphan desaturase for human plasmalogen synthesis.Science. 2019; 366: 128-132Crossref PubMed Scopus (31) Google Scholar, 8Werner E.R. Keller M.A. Sailer S. Lackner K. Koch J. Hermann M. Coassin S. Golderer G. Werner-Felmayer G. Zoeller R.A. et al.The TMEM189 gene encodes plasmanylethanolamine desaturase which introduces the characteristic vinyl ether double bond into plasmalogens.Proc. Natl. Acad. Sci. USA. 2020; 117: 7792-7798Crossref PubMed Scopus (18) Google Scholar). CEPT1 is the first ethanolamine phosphotransferase whose gene was identified and was believed to be solely responsible for catalyzing the final step of the CDP-ethanolamine pathway. CEPT1 is distributed in the ER and nuclear membranes of CHO-K1 cells (9Henneberry A.L. Wright M.M. McMaster C.R. The major sites of cellular phospholipid synthesis and molecular determinants of fatty acid and lipid head group specificity.Mol. Biol. Cell. 2002; 13: 3148-3161Crossref PubMed Scopus (153) Google Scholar). Both CDP-ethanolamine and CDP-choline are substrates for CEPT1 (4Henneberry A.L. McMaster C.R. Cloning and expression of a human choline/ethanolaminephosphotransferase: synthesis of phosphatidylcholine and phosphatidylethanolamine.Biochem. J. 1999; 339: 291-298Crossref PubMed Scopus (85) Google Scholar), although kinetic analysis demonstrated that CEPT1 prefers CDP-choline over CDP-ethanolamine as the phosphobase donor. In vitro enzymatic assays also revealed that CEPT1 prefers DAG 18:1–18:1 > DAG 16:1–16:1, 16:0–18:1, 16:0–22:6 as lipid acceptors. Eight years after the molecular cloning of CEPT1, a gene encoding another ethanolamine phosphotransferase, EPT1, was identified by homology searches of the NCBI data bank with reference to the CDP-alcohol phosphatidyltransferase motif, a common motif conserved in phospholipid synthases (5Horibata Y. Hirabayashi Y. Identification and characterization of human ethanolaminephosphotransferase1.J. Lipid Res. 2007; 48: 503-508Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). EPT1 (also called selenoprotein I) specifically transfers CDP-ethanolamine as the phosphobase donor (5Horibata Y. Hirabayashi Y. Identification and characterization of human ethanolaminephosphotransferase1.J. Lipid Res. 2007; 48: 503-508Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). In humans, this enzyme is distributed primarily in brain, placenta, liver, and pancreas, followed by heart, skeletal muscle, lung, and kidney, although its cellular distribution remains unknown. We previously reported exon skipping in the EPT1 gene in a patient suffering from a neurodegenerative disorder (10Horibata Y. Elpeleg O. Eran A. Hirabayashi Y. Savitzki D. Tal G. Mandel H. Sugimoto H. EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans.J. Lipid Res. 2018; 59: 1015-1026Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). The patient's skin fibroblasts had decreased levels of PE molecular species such as 38:6, 38:4, 40:6, 40:5 and 40:4 and, and more a decreased of These results that EPT1 an important in the maintenance of plasmenyl-PE in Another EPT1 was reported in with a neurodegenerative A. F. A. J. J.E. et of EPT1 a disorder of Kennedy pathway phospholipid Google Scholar). the contribution of EPT1 and CEPT1 to the de novo biosynthesis of EP molecular species remains In the present we the intracellular distribution of EPT1 and CEPT1 and found that EPT1 is in the Golgi apparatus and CEPT1 is in the ER. We and HEK293 cells and the de novo biosynthesis of EP molecular species in these cells radio- and deuterium-labeled These labeling demonstrated that EPT1 preferentially plasmenyl-PE and PE molecular species such as 36:1, 38:5, 38:4, 38:3, 40:6, 40:5, and whereas CEPT1 is important for the biosynthesis of PE molecular species such as 32:2, 32:1, 34:2, and 34:1. in vitro substrate for lipid acceptors revealed that EPT1 AAG 16–20:4 > DAG 18:0–20:4 > DAG 16:0–18:1 = AAG In contrast, CEPT1 DAG 16:0–18:1 more preferentially with other lipid acceptors. These results suggest that EPT1 and CEPT1 are distributed in different in cells and to the synthesis of different of EP molecular species. HEK293 cells in with in a containing generate and HEK293 cells as CEPT1 EPT1 and into the with these to the the cells, containing EPT1 and CEPT1 into the HEK293 cells the after the cells in the of 1 for and then cells as in and by enzyme was from the cells and the the by The for and for After a into of an and a EPT1 and CEPT1 with a the by and into the on with 1% into cells the cells with encoding a with the ER of After the cells with in for with with for and then with for The cells then with and followed by and with with or for 1 with with a The cells with expression containing EPT1 or CEPT1 and for with transferred to membranes a transfer and then the membranes with in for 1 and with containing The membranes then with with and then with for 1 The membranes with and with substrate to the and a For labeling of EPs with cells in containing of for with A a of for and then with in the of for from the cells the and A of total lipid and J. PubMed Scopus Google Scholar). phospholipids to and with plasmenyl-PE and PE, the to for development to the 1-alkenyl group in The of PE and the of PE from plasmenyl-PE a and EPs with deuterium-labeled ethanolamine by cells in containing 1 for After with the cells in and the of was a from containing of the and in the of of PE and by an and to a A of A containing and containing was The was as B. The was and the was EP species in by the of the phospholipid species and the of in For deuterium-labeled the of was plasmenyl-PE containing and the the of and as in of plasmalogen PubMed Scopus Google Scholar). and the and of Ethanolamine phosphotransferase was as previously (5Horibata Y. Hirabayashi Y. Identification and characterization of human ethanolaminephosphotransferase1.J. Lipid Res. 2007; 48: 503-508Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, Y. Elpeleg O. Eran A. Hirabayashi Y. Savitzki D. Tal G. Mandel H. Sugimoto H. EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans.J. Lipid Res. 2018; 59: 1015-1026Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). cells in containing of and in an for The content was a The 1 CDP-ethanolamine and DAG 18:1–18:1 DAG 16:0–18:1 or DAG 18:0–20:4 AAG 16–18:1 and AAG 16–20:4 as After for the was by of and then was After for the was to and as AAG was by plasmanyl-PC with A. from PubMed Scopus Google Scholar). 1 of or was in 1 of containing of from type and of ether After for 1 with the ether containing AAG was data are as was the or with A of was In mammalian cells, CEPT1 was reported to be distributed in the ER and nuclear (9Henneberry A.L. Wright M.M. McMaster C.R. The major sites of cellular phospholipid synthesis and molecular determinants of fatty acid and lipid head group specificity.Mol. Biol. Cell. 2002; 13: 3148-3161Crossref PubMed Scopus (153) Google Scholar). In contrast, have the intracellular localization of EPT1, in the in which the enzyme is found in the ER M. A. and phosphatidylcholine biosynthesis by the Kennedy pathway different sites in 2015; PubMed Scopus Google Scholar). the intracellular distribution of CEPT1 and EPT1 in mammalian cells, the enzymes with a the and in HEK293 cells, with followed by its second in the of CEPT1 was with the of indicating that the enzyme is distributed in the ER. In contrast, the of EPT1 was with indicating that the enzyme is in the Golgi apparatus (Fig. These results suggest that the intracellular sites for the production of EP by EPT1 or CEPT1 are We the of EPT1 and CEPT1 to EP molecular species by and cells the In vitro phosphotransferase was as an enzyme CDP-ethanolamine as a phosphoethanolamine and DAG 18:1–18:1 as a lipid PE was by (Fig. and the of lipid was (Fig. The results that the phosphotransferase in and by and of that of cells, respectively. These results suggest that the contribution of EPT1 in PE biosynthesis is than that of CEPT1. PE was in the cells, that the total of phosphotransferase in HEK293 cells is from EPT1 and CEPT1. The de novo biosynthesis of EP was by labeling with We the contribution of the CDP-ethanolamine pathway for the biosynthesis of EP by cells the is an enzyme responsible for the biosynthesis of CDP-ethanolamine. and cells in the of The lipid from the cells and was from PE by the to to the in plasmenyl-PE in formation of the of the lipid M.M. of of Lipid Res. Full Text PDF PubMed Google Scholar). in the of plasmenyl-PE to the PE PE with different PE and PE in the and cells, respectively. The cells preferentially whereas cells (Fig. These results suggest that EPT1 and CEPT1 to the biosynthesis of different PE molecular species. The of plasmenyl-PE was not in the and cells (Fig. that the production of plasmenyl-PE in HEK293 cells is mainly on Both PE and the of plasmenyl-PE in the and cells, that the CDP-ethanolamine pathway was in these cells. The results of labeling with ethanolamine suggest that EPT1 preferentially synthesizes and plasmenyl-PE, whereas CEPT1 preferentially (Fig. these expression of EPT1 or CEPT1 with a the into the cells. by in cells with CEPT1 or For the molecular of was than the molecular of CEPT1 or EPT1 The cells then with and the phospholipids and by in was present in the cells. and plasmenyl-PE also synthesized in the cells. The of the lipid as in The production of plasmenyl-PE by EPT1 was significantly than that by CEPT1 (Fig. These results that CEPT1 and EPT1 preferentially de novo and respectively. The of a phospholipid on a is to its that and shorter and fatty respectively. we in the EP molecular species after labeling with The deuterium-labeled EPs be from by of a After and cells with the PE and plasmenyl-PE molecular species by in the cells significantly PE molecular species, such as 32:2, 32:1, 34:2, and with the cells. In contrast, the cells significantly PE molecular species with fatty such as 36:1, 38:5, 38:4, 38:3, 40:6, 40:5, and with the cells. We these results by the with cells with EPT1 or CEPT1. in the cells preferentially synthesized PE molecular species containing 32:2, 32:1, 34:2, and with cells. the other cells significantly PE molecular species 36:1, 38:6, 38:5, 38:4, and with cells. These results the that EPT1 and CEPT1 preferentially produce PE molecular species containing and shorter fatty respectively. we the deuterium-labeled plasmenyl-PE molecular species. in and the and cells of plasmenyl-PE molecular species than and cells. these results that the biosynthesis of plasmenyl-PE is on We the of PE molecular species in and cells. in was and cells, for PE In cells, the levels of PE molecular species, such as 34:2, and 36:1, significantly decreased with the content of PE and PE in cells was significantly with cells. These results suggest that of EPT1 or CEPT1 on the levels of PE molecular species. We then the of plasmenyl-PE molecular species. in was and cells. the levels of plasmenyl-PE molecular species in and cells with cells, that EPT1 is more important for the of plasmenyl-PE than is CEPT1. The of PC and plasmanyl-PC molecular species also and cells. was in the of PC whereas in the levels of plasmanyl-PC molecular species in the and cells These results that EPT1 is also involved in of the plasmanyl-PC in EPT1 and CEPT1 are in the Golgi apparatus and the respectively. the that the synthesis of and plasmenyl-PE by EPT1 and by CEPT1 is on the in their subcellular we the of which of the Golgi with the ER. After with CEPT1 or EPT1, cells with and the intracellular distribution of these enzymes was by in the location of was after treatment as in R. G. of a Biol. PubMed Scopus Google Scholar). EPT1 was with the after indicating that the localization of EPT1 was from the Golgi apparatus to the ER In contrast, CEPT1 was distributed in the ER and after treatment EP was then with ethanolamine in the of in treatment did not in the of of CEPT1 in cells, or in and plasmenyl-PE of EPT1 in cells. results with and cells with in the of (Fig. The of on the de novo biosynthesis of PE molecular species was also by labeling with in the of PE molecular species in (Fig. and cells (Fig. or in plasmenyl-PE molecular species and These results suggest that subcellular localization is not important for the synthesis of PE and plasmenyl-PE molecular species by EPT1 and CEPT1. We that the synthesis of EP molecular species is on enzymatic lipid acceptors by ethanolamine phosphotransferase two DAG molecular species. and DAG 18:0–20:4 are DAG molecular species of and (Fig. We not enzyme for this after and and from cells EPT1 or CEPT1 as enzyme We the by the DAG 18:0–20:4 and DAG in and EPT1 but significantly DAG 18:0–20:4 with DAG 16:0–18:1 as a lipid In contrast, CEPT1 DAG 16:0–18:1 as a lipid with DAG 18:0–20:4 (Fig. These results that EPT1 preferentially CEPT1 We to the of EPT1 and CEPT1 AAG. AAG is not and AAG 16–18:1 and AAG 16–20:4 by plasmanyl-PC 16–18:1 and plasmanyl-PC we the AAG 16–18:1 and AAG 16–20:4 with DAG in the of EPT1 followed the AAG 16–20:4 > DAG 18:0–20:4 > DAG 16:0–18:1 = AAG In contrast, CEPT1 preferentially DAG 16:0–18:1 over other acceptors. these results suggest that the synthesis of EP molecular species by EPT1 and CEPT1 is on in enzymatic lipid acceptors. The final step of EP generation the CDP-ethanolamine pathway is catalyzed by EPT1 and CEPT1 but in the EP molecular species synthesized by enzyme In this labeling with ethanolamine demonstrated for the first that EPT1 is distributed in the Golgi apparatus and preferentially and plasmanyl-PE, CEPT1 is distributed in the ER and preferentially synthesizes A the main of this is in was decreased in the of PE molecular species and cells (Fig. likely the levels of PE are by CEPT1 or EPT1, and by another such as and by PE in PE molecular species, such as 34:2, and 36:1, in cells, that the CDP-ethanolamine pathway is critical for these PE molecular species. PE and PE significantly in cells with cells, for unknown. preferentially PE molecular species with polyunsaturated fatty PE 18:0–20:4 (3Bleijerveld O.B. Brouwers J.F. Vaandrager A.B. Helms J.B. Houweling M. The CDP-ethanolamine pathway and phosphatidylserine decarboxylation generate different phosphatidylethanolamine molecular species.J. Biol. Chem. 2007; 282: 28362-28372Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). we that the pathway is and these PE molecular species to for the of PE by the CDP-ethanolamine pathway. We previously found that the of plasmenyl-PE is significantly in skin fibroblasts from a patient with exon skipping in the EPT1 gene (10Horibata Y. Elpeleg O. Eran A. Hirabayashi Y. Savitzki D. Tal G. Mandel H. Sugimoto H. EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans.J. Lipid Res. 2018; 59: 1015-1026Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). In the present we demonstrated that EPT1, but not CEPT1, is responsible for the maintenance of plasmenyl-PE (Fig. CEPT1 plasmanyl-PE in vitro (Fig. its enzymatic is likely for the biosynthesis of plasmanyl-PE in cells. We suggest two EPT1 a contribution than CEPT1 to the of plasmenyl-PE in cells. EPT1 enzymatic than CEPT1 in cells (Fig. and is a in enzymatic lipid EPT1 greatly prefers AAG with CEPT1 (Fig. The molecular the different of EPT1 and CEPT1 their lipid acceptors and phosphobase remains and the of these The plasmenyl-PE was not in and cells (Fig. although the synthesis of plasmenyl-PE from ethanolamine was These results suggest the of a pathway other than the CDP-ethanolamine pathway for the synthesis of plasmanyl-PE and have demonstrated that serine be into the head group of PS and the head group of plasmanyl-PE and plasmenyl-PE and ethanolamine into different plasmalogen subcellular analyses of synthesis in Res. PubMed Scopus Google Scholar, E. of phospholipid in cells from in into serine base and decarboxylation Biol. Chem. Full Text PDF PubMed Google Scholar, M.A. A.A. The of ethanolamine and serine for ethanolamine synthesis by human Biol. Chem. Full Text PDF PubMed Google Scholar). In are the of in D. K. of and and fatty Lipid Res. Full Text Full Text PDF PubMed Google Scholar), Identification of abundant ether in the human by Chem. PubMed Scopus Google Scholar), Identification of ether-linked species in by Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar), and K. O. F. of in human and of species with Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). the pathway for of the CDP-ethanolamine pathway. is to the pathway, or synthesizes We previously found levels of plasmanyl-PC in patient cells with EPT1 (10Horibata Y. Elpeleg O. Eran A. Hirabayashi Y. Savitzki D. Tal G. Mandel H. Sugimoto H. EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans.J. Lipid Res. 2018; 59: 1015-1026Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar) and in and cells the of plasmanyl-PE synthesis a of AAG. CEPT1 and in cells, or in the cells, likely AAG to generate EPT1 is distributed in the Golgi and plasmanyl-PE, a for plasmenyl-PE, is likely in the Golgi apparatus after is then desaturated and to plasmenyl-PE by the of PEDS encoded by demonstrated that TMEM189 is in the ER (7Gallego-García A. Monera-Girona A.J. Pajares-Martinez E. Bastida-Martinez E. Perez-Castano R. Iniesta A.A. Fontes M. Padmanabhan S. Elias-Arnanz M. A bacterial light response reveals an orphan desaturase for human plasmalogen synthesis.Science. 2019; 366: 128-132Crossref PubMed Scopus (31) Google Scholar, 8Werner E.R. Keller M.A. Sailer S. Lackner K. Koch J. Hermann M. Coassin S. Golderer G. Werner-Felmayer G. Zoeller R.A. et al.The TMEM189 gene encodes plasmanylethanolamine desaturase which introduces the characteristic vinyl ether double bond into plasmalogens.Proc. Natl. Acad. Sci. USA. 2020; 117: 7792-7798Crossref PubMed Scopus (18) Google Scholar). These results suggest that plasmanyl-PE in the Golgi be transferred to the ER for by and then catalyzed to that the of is by of lipid transfer sites K. Lipid transfer and Lipid Res. 2018; 59: Full Text Full Text PDF PubMed Scopus Google Scholar). is likely transferred by In this demonstrated that EPT1 and CEPT1, the final enzymes for the synthesis of EP in the CDP-ethanolamine pathway, are distributed in the Golgi apparatus and respectively. EPT1 mainly to the biosynthesis of plasmenyl-PE and PE molecular species containing fatty such as 36:1, 38:5, 38:4, 38:3, 40:6, and 40:5, and CEPT1 preferentially PE containing shorter fatty such as 32:2, 32:1, 34:2, and 34:1. The to of the for with 1-alkyl-2-acyl-glycerol A choline/ethanolamine phosphotransferase 1 phosphate ethanolamine phospholipid ethanolamine phosphotransferase 1 CTP:phosphoethanolamine cytidylyltransferase plasmanyl-PE desaturase PE PE 1-alkyl-2-acyl-glycerophosphocholine 1-alkyl-2-acyl-glycerophosphoethanolamine 1-alkenyl-2-acyl-glycerophosphoethanolamine PS decarboxylase

Topics & Concepts