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.
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References
Aboagye EO, Bhujwalla ZM (1999) Malignant transformation alters membrane choline phospholipid metabolism of human mammary epithelial cells. Cancer Res 59:80–84
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 8:121–128
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-05-1338
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.M113.531921
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.2016.252
Buchman AL et al (1992) Lecithin increases plasma free choline and decreases hepatic steatosis in long-term total parenteral nutrition patients. Gastroenterology 102:1363–1370
Buchman AL et al (1995) Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology 22:1399–1403
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.2003257
Cheng M, Bhujwalla ZM, Glunde K (2016) Targeting phospholipid metabolism in cancer. Front Oncol 6:266. https://doi.org/10.3389/fonc.2016.00266
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/s41564-018-0294-4
Cho JH, Han JS (2017) Phospholipase D and its essential role in cancer. Mol Cell 40:805–813. https://doi.org/10.14348/molcells.2017.0241
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.x
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/nature12825
Dall’Armi C et al (2010) The phospholipase D1 pathway modulates macroautophagy. Nat Commun 1:142. https://doi.org/10.1038/ncomms1144
Daly PF, Lyon RC, Faustino PJ, Cohen JS (1987) Phospholipid metabolism in cancer cells monitored by 31P NMR spectroscopy. J Biol Chem 262:14875–14878
Davis KL, Berger PA, Hollister LE (1975) Letter: choline for tardive dyskinesia. N Engl J Med 293:152. https://doi.org/10.1056/nejm197507172930317
Ducker GS, Rabinowitz JD (2017) One-carbon metabolism in health and disease. Cell Metab 25:27–42. https://doi.org/10.1016/j.cmet.2016.08.009
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.62.4.911
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/135.4.826
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.28165
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.337
Glunde K, Bhujwalla ZM, Ronen SM (2011) Choline metabolism in malignant transformation. Nat Rev Cancer 11:835–848. https://doi.org/10.1038/nrc3162
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/10.1586/14737159.2015.1039515
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/nejm197709082971002
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)90055-2
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-16-0042
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.2013.207
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 59:3112–3118
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, Washington
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-11-0544
Kennedy EP, Weiss SB (1956) The function of cytidine coenzymes in the biosynthesis of phospholipids. J Biol Chem 222:193–214
Lacal JC (2001) Choline kinase: a novel target for antitumor drugs. IDrugs 4:419–426
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-14-0531
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.5180
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/jm100814g
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.43.5.452
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.2009.02.057
Li Z, Vance DE (2008) Phosphatidylcholine and choline homeostasis. J Lipid Res 49:1187–1194. https://doi.org/10.1194/jlr.R700019-JLR200
Lykidis A (2007) Comparative genomics and evolution of eukaryotic phospholipid biosynthesis. Prog Lipid Res 46:171–199. https://doi.org/10.1016/j.plipres.2007.03.003
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.2016.03.043
McDermott M, Wakelam MJ, Morris AJ (2004) Phospholipase D. Biochem Cell Biol 82:225–253. https://doi.org/10.1139/o03-079
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.115.011684
Meacham CE, Morrison SJ (2013) Tumour heterogeneity and cancer cell plasticity. Nature 501:328–337. https://doi.org/10.1038/nature12624
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/10.1038/211759b0
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.12956
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/22.10.1641
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.2007.01.059
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/bss0740247
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.00029.2002
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/jm301782e
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/s00018-006-6249-6
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/10.1042/0264-6021:3600707
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.2384
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.1205556
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 296:580–583
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/11.1.177
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.140
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/cb500828m
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/cr200296t
Shane B, Stokstad EL (1985) Vitamin B12-folate interrelationships. Annu Rev Nutr 5:115–141. https://doi.org/10.1146/annurev.nu.05.070185.000555
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.114.007955
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/83.1.5
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.24.012003.132418
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.x
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.108.053298
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.2015.10.030
Sundler R, Akesson B (1975) Regulation of phospholipid biosynthesis in isolated rat hepatocytes. Effect of different substrates. J Biol Chem 250:3359–3367
Ueland PM (2011) Choline and betaine in health and disease. J Inherit Metab Dis 34:3–15. https://doi.org/10.1007/s10545-010-9088-4
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.2010.08.018
Wang Z et al (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472:57–63. https://doi.org/10.1038/nature09922
Wood JL, Allison RG (1982) Effects of consumption of choline and lecithin on neurological and cardiovascular systems. Fed Proc 41:3015–3021
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-x
Zeisel SH (2009) Importance of methyl donors during reproduction. Am J Clin Nutr 89:673s–677s. https://doi.org/10.3945/ajcn.2008.26811D
Zeisel SH (2012a) A brief history of choline. Ann Nutr Metab 61:254–258. https://doi.org/10.1159/000343120
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.2011.10.008
Zeisel SH, Blusztajn JK (1994) Choline and human nutrition. Annu Rev Nutr 14:269–296. https://doi.org/10.1146/annurev.nu.14.070194.001413
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.x
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/133.5.1302
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.R114.576876
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/cb3005353
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/ncb1594
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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.
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Onono, F.O., Morris, A.J. (2019). Phospholipase D and Choline Metabolism. In: Gomez-Cambronero, J., Frohman, M. (eds) Lipid Signaling in Human Diseases. Handbook of Experimental Pharmacology, vol 259. Springer, Cham. https://doi.org/10.1007/164_2019_320
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