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Phospholipase D and Choline Metabolism

  • Fredrick O. Onono
  • Andrew J. MorrisEmail author
Chapter
  • 44 Downloads
Part of the Handbook of Experimental Pharmacology book series

Abstract

Phospholipases D (PLDs) catalyze hydrolysis of the diester bond of phospholipids to generate phosphatidic acid and the free lipid headgroup. In mammals, PLD enzymes comprise the intracellular enzymes PLD1 and PLD2 and possibly the proteins encoded by related genes, as well as a class of cell surface and secreted enzymes with structural homology to ectonucleotide phosphatases/phosphodiesterases as typified by autotaxin (ENPP2) that have lysoPLD activities. Genetic and pharmacological loss-of-function approaches implicate these enzymes in intra- and intercellular signaling mediated by the lipid products phosphatidic acid, lysophosphatidic acid, and their metabolites, while the possibility that the water-soluble product of their reactions is biologically relevant has received far less attention. PLD1 and PLD2 are highly selective for phosphatidylcholine (PC), whereas autotaxin has broader substrate specificity for lysophospholipids but by virtue of the high abundance of lysophosphatidylcholine (LPC) in extracellular fluids predominantly hydrolyses this substrate. In all cases, the water-soluble product of these PLD activities is choline. Although choline can be formed de novo by methylation of phosphatidylethanolamine, this activity is absent in most tissues, so mammals are effectively auxotrophic for choline. Dietary consumption of choline in both free and esterified forms is substantial. Choline is necessary for synthesis of the neurotransmitter acetylcholine and of the choline-containing phospholipids PC and sphingomyelin (SM) and also plays a recently appreciated important role as a methyl donor in the pathways of “one-carbon (1C)” metabolism. This review discusses emerging evidence that some of the biological functions of these intra- and extracellular PLD enzymes involve generation of choline with a particular focus on the possibility that these choline and PLD dependent processes are dysregulated in cancer.

Keywords

Choline One carbon metabolism Phospholipase D 

Notes

Acknowledgments

Research in the author’s laboratories is supported by grants from the NIH and the Department of Veterans Affairs. FOO is the recipient of an NIH/NCI Mentored Research Scientist Development Award K01CA197073.

References

  1. Aboagye EO, Bhujwalla ZM (1999) Malignant transformation alters membrane choline phospholipid metabolism of human mammary epithelial cells. Cancer Res 59:80–84Google Scholar
  2. Ahn MJ et al (2012) A single nucleotide polymorphism in the phospholipase D1 gene is associated with risk of non-small cell lung cancer. Int J Biomed Sci 8:121–128Google Scholar
  3. Al-Saffar NM et al (2006) Noninvasive magnetic resonance spectroscopic pharmacodynamic markers of the choline kinase inhibitor MN58b in human carcinoma models. Cancer Res 66:427–434.  https://doi.org/10.1158/0008-5472.Can-05-1338CrossRefGoogle Scholar
  4. Baba T et al (2014) Phosphatidic acid (PA)-preferring phospholipase A1 regulates mitochondrial dynamics. J Biol Chem 289:11497–11511.  https://doi.org/10.1074/jbc.M113.531921CrossRefGoogle Scholar
  5. Brown HA, Thomas PG, Lindsley CW (2017) Targeting phospholipase D in cancer, infection and neurodegenerative disorders. Nat Rev Drug Discov 16:351–367.  https://doi.org/10.1038/nrd.2016.252CrossRefGoogle Scholar
  6. Buchman AL et al (1992) Lecithin increases plasma free choline and decreases hepatic steatosis in long-term total parenteral nutrition patients. Gastroenterology 102:1363–1370Google Scholar
  7. Buchman AL et al (1995) Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology 22:1399–1403Google Scholar
  8. Chen Q et al (2012) Key roles for the lipid signaling enzyme phospholipase D1 in the tumor microenvironment during tumor angiogenesis and metastasis. Sci Signal 5:ra79.  https://doi.org/10.1126/scisignal.2003257CrossRefGoogle Scholar
  9. Cheng M, Bhujwalla ZM, Glunde K (2016) Targeting phospholipid metabolism in cancer. Front Oncol 6:266.  https://doi.org/10.3389/fonc.2016.00266CrossRefGoogle Scholar
  10. Chittim CL, Martinez Del Campo A, Balskus EP (2019) Gut bacterial phospholipase Ds support disease-associated metabolism by generating choline. Nat Microbiol 4:155–163.  https://doi.org/10.1038/s41564-018-0294-4CrossRefGoogle Scholar
  11. Cho JH, Han JS (2017) Phospholipase D and its essential role in cancer. Mol Cell 40:805–813.  https://doi.org/10.14348/molcells.2017.0241CrossRefGoogle Scholar
  12. Choi WS, Chahdi A, Kim YM, Fraundorfer PF, Beaven MA (2002) Regulation of phospholipase D and secretion in mast cells by protein kinase A and other protein kinases. Ann N Y Acad Sci 968:198–212.  https://doi.org/10.1111/j.1749-6632.2002.tb04336.xCrossRefGoogle Scholar
  13. Cruchaga C et al (2014) Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease. Nature 505:550–554.  https://doi.org/10.1038/nature12825CrossRefGoogle Scholar
  14. Dall’Armi C et al (2010) The phospholipase D1 pathway modulates macroautophagy. Nat Commun 1:142.  https://doi.org/10.1038/ncomms1144CrossRefGoogle Scholar
  15. Daly PF, Lyon RC, Faustino PJ, Cohen JS (1987) Phospholipid metabolism in cancer cells monitored by 31P NMR spectroscopy. J Biol Chem 262:14875–14878Google Scholar
  16. Davis KL, Berger PA, Hollister LE (1975) Letter: choline for tardive dyskinesia. N Engl J Med 293:152.  https://doi.org/10.1056/nejm197507172930317CrossRefGoogle Scholar
  17. Ducker GS, Rabinowitz JD (2017) One-carbon metabolism in health and disease. Cell Metab 25:27–42.  https://doi.org/10.1016/j.cmet.2016.08.009CrossRefGoogle Scholar
  18. Eisen SF, Brown HA (2002) Selective estrogen receptor (ER) modulators differentially regulate phospholipase D catalytic activity in ER-negative breast cancer cells. Mol Pharmacol 62:911–920.  https://doi.org/10.1124/mol.62.4.911CrossRefGoogle Scholar
  19. Fischer LM et al (2005) Ad libitum choline intake in healthy individuals meets or exceeds the proposed adequate intake level. J Nutr 135:826–829.  https://doi.org/10.1093/jn/135.4.826CrossRefGoogle Scholar
  20. Gadiya M et al (2014) Phospholipase D1 and choline kinase-alpha are interactive targets in breast cancer. Cancer Biol Ther 15:593–601.  https://doi.org/10.4161/cbt.28165CrossRefGoogle Scholar
  21. Gibellini F, Smith TK (2010) The Kennedy pathway – de novo synthesis of phosphatidylethanolamine and phosphatidylcholine. IUBMB Life 62:414–428.  https://doi.org/10.1002/iub.337CrossRefGoogle Scholar
  22. Glunde K, Bhujwalla ZM, Ronen SM (2011) Choline metabolism in malignant transformation. Nat Rev Cancer 11:835–848.  https://doi.org/10.1038/nrc3162CrossRefGoogle Scholar
  23. Glunde K, Penet MF, Jiang L, Jacobs MA, Bhujwalla ZM (2015) Choline metabolism-based molecular diagnosis of cancer: an update. Expert Rev Mol Diagn 15:735–747.  https://doi.org/10.1586/14737159.2015.1039515CrossRefGoogle Scholar
  24. Growdon JH, Hirsch MJ, Wurtman RJ, Wiener W (1977) Oral choline administration to patients with tardive dyskinesia. N Engl J Med 297:524–527.  https://doi.org/10.1056/nejm197709082971002CrossRefGoogle Scholar
  25. Hamza M, Lloveras J, Ribbes G, Soula G, Douste-Blazy L (1983) An in vitro study of hemicholinium-3 on phospholipid metabolism of Krebs II ascites cells. Biochem Pharmacol 32:1893–1897.  https://doi.org/10.1016/0006-2952(83)90055-2CrossRefGoogle Scholar
  26. Hanley MP, Kadaveru K, Perret C, Giardina C, Rosenberg DW (2016) Dietary methyl donor depletion suppresses intestinal adenoma development. Cancer Prevent Res 9:812–820.  https://doi.org/10.1158/1940-6207.capr-16-0042CrossRefGoogle Scholar
  27. Henkels KM, Boivin GP, Dudley ES, Berberich SJ, Gomez-Cambronero J (2013) Phospholipase D (PLD) drives cell invasion, tumor growth and metastasis in a human breast cancer xenograph model. Oncogene 32:5551–5562.  https://doi.org/10.1038/onc.2013.207CrossRefGoogle Scholar
  28. Hernandez-Alcoceba R, Fernandez F, Lacal JC (1999) In vivo antitumor activity of choline kinase inhibitors: a novel target for anticancer drug discovery. Cancer Res 59:3112–3118Google Scholar
  29. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline (1998) Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. National Academies Press (US) National Academy of Sciences, WashingtonGoogle Scholar
  30. Kadaveru K, Protiva P, Greenspan EJ, Kim YI, Rosenberg DW (2012) Dietary methyl donor depletion protects against intestinal tumorigenesis in Apc(Min/+) mice. Cancer Prevent Res 5:911–920.  https://doi.org/10.1158/1940-6207.capr-11-0544CrossRefGoogle Scholar
  31. Kennedy EP, Weiss SB (1956) The function of cytidine coenzymes in the biosynthesis of phospholipids. J Biol Chem 222:193–214Google Scholar
  32. Lacal JC (2001) Choline kinase: a novel target for antitumor drugs. IDrugs 4:419–426Google Scholar
  33. Lacal JC, Campos JM (2015) Preclinical characterization of RSM-932A, a novel anticancer drug targeting the human choline kinase alpha, an enzyme involved in increased lipid metabolism of cancer cells. Mol Cancer Ther 14:31–39.  https://doi.org/10.1158/1535-7163.Mct-14-0531CrossRefGoogle Scholar
  34. Lamming DW et al (2015) Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model. Oncotarget 6:31233–31240.  https://doi.org/10.18632/oncotarget.5180CrossRefGoogle Scholar
  35. Lavieri RR et al (2010) Design, synthesis, and biological evaluation of halogenated N-(2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)ethyl)benzamides: discovery of an isoform-selective small molecule phospholipase D2 inhibitor. J Med Chem 53:6706–6719.  https://doi.org/10.1021/jm100814gCrossRefGoogle Scholar
  36. Lawrence CM, Millac P, Stout GS, Ward JW (1980) The use of choline chloride in ataxic disorders. J Neurol Neurosurg Psychiatry 43:452–454.  https://doi.org/10.1136/jnnp.43.5.452CrossRefGoogle Scholar
  37. Lewis JA et al (2009) Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part I: impact of alternative halogenated privileged structures for PLD1 specificity. Bioorg Med Chem Lett 19:1916–1920.  https://doi.org/10.1016/j.bmcl.2009.02.057CrossRefGoogle Scholar
  38. Li Z, Vance DE (2008) Phosphatidylcholine and choline homeostasis. J Lipid Res 49:1187–1194.  https://doi.org/10.1194/jlr.R700019-JLR200CrossRefGoogle Scholar
  39. Lykidis A (2007) Comparative genomics and evolution of eukaryotic phospholipid biosynthesis. Prog Lipid Res 46:171–199.  https://doi.org/10.1016/j.plipres.2007.03.003CrossRefGoogle Scholar
  40. Marjon K et al (2016) MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Rep 15:574–587.  https://doi.org/10.1016/j.celrep.2016.03.043CrossRefGoogle Scholar
  41. McDermott M, Wakelam MJ, Morris AJ (2004) Phospholipase D. Biochem Cell Biol 82:225–253.  https://doi.org/10.1139/o03-079CrossRefGoogle Scholar
  42. McGuire S (2016) Scientific report of the 2015 Dietary Guidelines Advisory Committee. Washington, DC: US Departments of Agriculture and Health and Human Services, 2015. Adv Nutr 7:202–204.  https://doi.org/10.3945/an.115.011684CrossRefGoogle Scholar
  43. Meacham CE, Morrison SJ (2013) Tumour heterogeneity and cancer cell plasticity. Nature 501:328–337.  https://doi.org/10.1038/nature12624CrossRefGoogle Scholar
  44. Mehendale HM, Dauterman WC, Hodgson E (1966) Phosphatidyl carnitine: a possible intermediate in the biosynthesis of phosphatidyl beta-methylcholine in Phormia regina (Meigen). Nature 211:759–761.  https://doi.org/10.1038/211759b0CrossRefGoogle Scholar
  45. Mentch SJ, Locasale JW (2016) One-carbon metabolism and epigenetics: understanding the specificity. Ann N Y Acad Sci 1363:91–98.  https://doi.org/10.1111/nyas.12956CrossRefGoogle Scholar
  46. Min DS et al (2001) Neoplastic transformation and tumorigenesis associated with overexpression of phospholipase D isozymes in cultured murine fibroblasts. Carcinogenesis 22:1641–1647.  https://doi.org/10.1093/carcin/22.10.1641CrossRefGoogle Scholar
  47. Monovich L et al (2007) Optimization of halopemide for phospholipase D2 inhibition. Bioorg Med Chem Lett 17:2310–2311.  https://doi.org/10.1016/j.bmcl.2007.01.059CrossRefGoogle Scholar
  48. Morris AJ (2007) Regulation of phospholipase D activity, membrane targeting and intracellular trafficking by phosphoinositides. Biochem Soc Symp 74:247–257.  https://doi.org/10.1042/bss0740247CrossRefGoogle Scholar
  49. Nanjundan M, Possmayer F (2003) Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase. Am J Physiol Lung Cell Mol Physiol 284:L1–L23.  https://doi.org/10.1152/ajplung.00029.2002CrossRefGoogle Scholar
  50. O’Reilly MC et al (2013) Development of dual PLD1/2 and PLD2 selective inhibitors from a common 1,3,8-triazaspiro[4.5]decane core: discovery of Ml298 and Ml299 that decrease invasive migration in U87-MG glioblastoma cells. J Med Chem 56:2695–2699.  https://doi.org/10.1021/jm301782eCrossRefGoogle Scholar
  51. Pajares MA, Perez-Sala D (2006) Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism? Cell Mol Life Sci 63:2792–2803.  https://doi.org/10.1007/s00018-006-6249-6CrossRefGoogle Scholar
  52. Pettitt TR, McDermott M, Saqib KM, Shimwell N, Wakelam MJ (2001) Phospholipase D1b and D2a generate structurally identical phosphatidic acid species in mammalian cells. Biochem J 360:707–715.  https://doi.org/10.1042/0264-6021:3600707CrossRefGoogle Scholar
  53. Quinlan CL et al (2017) Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A. Nat Chem Biol 13:785–792.  https://doi.org/10.1038/nchembio.2384CrossRefGoogle Scholar
  54. Ramirez de Molina A et al (2002a) Increased choline kinase activity in human breast carcinomas: clinical evidence for a potential novel antitumor strategy. Oncogene 21:4317–4322.  https://doi.org/10.1038/sj.onc.1205556CrossRefGoogle Scholar
  55. Ramirez de Molina A et al (2002b) Overexpression of choline kinase is a frequent feature in human tumor-derived cell lines and in lung, prostate, and colorectal human cancers. Biochem Biophys Res Commun 296:580–583Google Scholar
  56. Schrager TF, Newberne PM, Pikul AH, Groopman JD (1990) Aflatoxin-DNA adduct formation in chronically dosed rats fed a choline-deficient diet. Carcinogenesis 11:177–180.  https://doi.org/10.1093/carcin/11.1.177CrossRefGoogle Scholar
  57. Scott SA et al (2009) Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness. Nat Chem Biol 5:108–117.  https://doi.org/10.1038/nchembio.140CrossRefGoogle Scholar
  58. Scott SA et al (2015) Discovery of desketoraloxifene analogues as inhibitors of mammalian, Pseudomonas aeruginosa, and NAPE phospholipase D enzymes. ACS Chem Biol 10:421–432.  https://doi.org/10.1021/cb500828mCrossRefGoogle Scholar
  59. Selvy PE, Lavieri RR, Lindsley CW, Brown HA (2011) Phospholipase D: enzymology, functionality, and chemical modulation. Chem Rev 111:6064–6119.  https://doi.org/10.1021/cr200296tCrossRefGoogle Scholar
  60. Shane B, Stokstad EL (1985) Vitamin B12-folate interrelationships. Annu Rev Nutr 5:115–141.  https://doi.org/10.1146/annurev.nu.05.070185.000555CrossRefGoogle Scholar
  61. Sherriff JL, O’Sullivan TA, Properzi C, Oddo JL, Adams LA (2016) Choline, its potential role in nonalcoholic fatty liver disease, and the case for human and bacterial genes. Adv Nutr 7:5–13.  https://doi.org/10.3945/an.114.007955CrossRefGoogle Scholar
  62. Stead LM, Brosnan JT, Brosnan ME, Vance DE, Jacobs RL (2006) Is it time to reevaluate methyl balance in humans? Am J Clin Nutr 83:5–10.  https://doi.org/10.1093/ajcn/83.1.5CrossRefGoogle Scholar
  63. Stipanuk MH (2004) Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine. Annu Rev Nutr 24:539–577.  https://doi.org/10.1146/annurev.nutr.24.012003.132418CrossRefGoogle Scholar
  64. Stover PJ (2004) Physiology of folate and vitamin B12 in health and disease. Nutr Rev 62:S3–S12. Discussion S13.  https://doi.org/10.1111/j.1753-4887.2004.tb00070.xGoogle Scholar
  65. Su W et al (2009) 5-Fluoro-2-indolyl des-chlorohalopemide (FIPI), a phospholipase D pharmacological inhibitor that alters cell spreading and inhibits chemotaxis. Mol Pharmacol 75:437–446.  https://doi.org/10.1124/mol.108.053298CrossRefGoogle Scholar
  66. Su X, Wellen KE, Rabinowitz JD (2016) Metabolic control of methylation and acetylation. Curr Opin Chem Biol 30:52–60.  https://doi.org/10.1016/j.cbpa.2015.10.030CrossRefGoogle Scholar
  67. Sundler R, Akesson B (1975) Regulation of phospholipid biosynthesis in isolated rat hepatocytes. Effect of different substrates. J Biol Chem 250:3359–3367Google Scholar
  68. Ueland PM (2011) Choline and betaine in health and disease. J Inherit Metab Dis 34:3–15.  https://doi.org/10.1007/s10545-010-9088-4CrossRefGoogle Scholar
  69. Van Horn L (2010) Development of the 2010 US Dietary Guidelines Advisory Committee Report: perspectives from a registered dietitian. J Am Diet Assoc 110:1638–1645.  https://doi.org/10.1016/j.jada.2010.08.018CrossRefGoogle Scholar
  70. Wang Z et al (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472:57–63.  https://doi.org/10.1038/nature09922CrossRefGoogle Scholar
  71. Wood JL, Allison RG (1982) Effects of consumption of choline and lecithin on neurological and cardiovascular systems. Fed Proc 41:3015–3021Google Scholar
  72. Yamada Y et al (2003) Association of a polymorphism of the phospholipase D2 gene with the prevalence of colorectal cancer. J Mol Med 81:126–131.  https://doi.org/10.1007/s00109-002-0411-xCrossRefGoogle Scholar
  73. Zeisel SH (2009) Importance of methyl donors during reproduction. Am J Clin Nutr 89:673s–677s.  https://doi.org/10.3945/ajcn.2008.26811DCrossRefGoogle Scholar
  74. Zeisel SH (2012a) A brief history of choline. Ann Nutr Metab 61:254–258.  https://doi.org/10.1159/000343120CrossRefGoogle Scholar
  75. Zeisel SH (2012b) Dietary choline deficiency causes DNA strand breaks and alters epigenetic marks on DNA and histones. Mutat Res 733:34–38.  https://doi.org/10.1016/j.mrfmmm.2011.10.008CrossRefGoogle Scholar
  76. Zeisel SH, Blusztajn JK (1994) Choline and human nutrition. Annu Rev Nutr 14:269–296.  https://doi.org/10.1146/annurev.nu.14.070194.001413CrossRefGoogle Scholar
  77. Zeisel SH, da Costa KA (2009) Choline: an essential nutrient for public health. Nutr Rev 67:615–623.  https://doi.org/10.1111/j.1753-4887.2009.00246.xCrossRefGoogle Scholar
  78. Zeisel SH, Mar MH, Howe JC, Holden JM (2003) Concentrations of choline-containing compounds and betaine in common foods. J Nutr 133:1302–1307.  https://doi.org/10.1093/jn/133.5.1302CrossRefGoogle Scholar
  79. Zhang Y, Frohman MA (2014) Cellular and physiological roles for phospholipase D1 in cancer. J Biol Chem 289:22567–22574.  https://doi.org/10.1074/jbc.R114.576876CrossRefGoogle Scholar
  80. Zhang W et al (2013) Fluorinated N,N-dialkylaminostilbenes repress colon cancer by targeting methionine S-adenosyltransferase 2A. ACS Chem Biol 8:796–803.  https://doi.org/10.1021/cb3005353CrossRefGoogle Scholar
  81. Zhao C, Du G, Skowronek K, Frohman MA, Bar-Sagi D (2007) Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos. Nat Cell Biol 9:706–712.  https://doi.org/10.1038/ncb1594CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Cardiovascular MedicineThe Gill Heart and Vascular Institute, University of Kentucky College of MedicineLexingtonUSA
  2. 2.Lexington Veterans Affairs Medical CenterLexingtonUSA

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