Phosphatidylcholine-specific phospholipase D (PLD, EC 3.1.4.4) catalyses the formation of phosphatidic acid from phosphatidylcholine. In addition, the enzyme can make use of alcohols, such as butanol in a transphosphatidylation reaction [13].

A lysophospholipase D activity (ENPP2, Q13822, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2, phosphodiesterase I, nucleotide pyrophosphatase 2, autotaxin) has been described, which not only catalyses the production of lysophosphatidic acid (LPA) from lysophosphatidylcholine, but also cleaves ATP (see Goding et al., 2003 [1]). Additionally, an N-acylethanolamine-specific phospholipase D (NAPEPLD, Q6IQ20) has been characterized, which appears to have a role in the generation of endocannabinoids/endovanilloids, including anandamide [9]. This enzyme activity appears to be enhanced by polyamines in the physiological range [4] and fails to transphosphatidylate with alcohols [11].

Three further, less well-characterised isoforms are PLD3 (PLD3, Q8IV08, other names Choline phosphatase 3, HindIII K4L homolog, Hu-K4), PLD4 (PLD4, Q96BZ4, other names Choline phosphatase 4, Phosphatidylcholine-hydrolyzing phospholipase, D4C14orf175 UNQ2488/PRO5775) and PLD5 (PLD5, Q8N7P1). PLD3 has been reported to be involved in myogenesis [10]. PLD4 is described not to have phospholipase D catalytic activity [19], but has been associated with inflammatory disorders [8,16-17]. Recessive, loss-of-function mutations in PLD4 have been identified as causative in patients with systemic lupus erythematosus (SLE) [18]. PLD4 dysfunction leads to accumulation of ssDNA which triggers uncontrolled activation of TLR7/TLR9, and a surge in IFN and autoantibody production [7]. Sequence analysis suggests that PLD5 is catalytically inactive.

* Key recommended reading is highlighted with an asterisk

* Brown HA, Thomas PG, Lindsley CW. (2017) Targeting phospholipase D in cancer, infection and neurodegenerative disorders. Nat Rev Drug Discov, 16 (5): 351-367. [PMID:28209987]

Frohman MA. (2015) The phospholipase D superfamily as therapeutic targets. Trends Pharmacol Sci, 36 (3): 137-44. [PMID:25661257]

* McDermott MI, Wang Y, Wakelam MJO, Bankaitis VA. (2020) Mammalian phospholipase D: Function, and therapeutics. Prog Lipid Res, 78: 101018. [PMID:31830503]

Nelson RK, Frohman MA. (2015) Physiological and pathophysiological roles for phospholipase D. J Lipid Res, 56 (12): 2229-37. [PMID:25926691]

* Onono FO, Morris AJ. (2020) Phospholipase D and Choline Metabolism. Handb Exp Pharmacol, 259: 205-218. [PMID:32086667]

* Yao Y, Li J, Lin Y, Zhou J, Zhang P, Xu Y. (2021) Structural insights into phospholipase D function. Prog Lipid Res, 81: 101070. [PMID:33181180]

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2. Hammond SM, Jenco JM, Nakashima S, Cadwallader K, Gu Q, Cook S, Nozawa Y, Prestwich GD, Frohman MA, Morris AJ. (1997) Characterization of two alternately spliced forms of phospholipase D1. Activation of the purified enzymes by phosphatidylinositol 4,5-bisphosphate, ADP-ribosylation factor, and Rho family monomeric GTP-binding proteins and protein kinase C-alpha. J Biol Chem, 272 (6): 3860-8. [PMID:9013646]

3. Lavieri RR, Scott SA, Selvy PE, Kim K, Jadhav S, Morrison RD, Daniels JS, Brown HA, Lindsley CW. (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 (18): 6706-19. [PMID:20735042]

4. Liu Q, Tonai T, Ueda N. (2002) Activation of N-acylethanolamine-releasing phospholipase D by polyamines. Chem Phys Lipids, 115 (1-2): 77-84. [PMID:12047899]

5. Lopez I, Arnold RS, Lambeth JD. (1998) Cloning and initial characterization of a human phospholipase D2 (hPLD2). ADP-ribosylation factor regulates hPLD2. J Biol Chem, 273 (21): 12846-52. [PMID:9582313]

6. Luo JQ, Liu X, Hammond SM, Colley WC, Feig LA, Frohman MA, Morris AJ, Foster DA. (1997) RalA interacts directly with the Arf-responsive, PIP2-dependent phospholipase D1. Biochem Biophys Res Commun, 235 (3): 854-9. [PMID:9207251]

7. McHugh J. (2025) PLD4 variants promote SLE via unchecked TLR activation. Nat Rev Rheumatol, 21 (12): 697. [PMID:41168358]

8. Okada Y, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, Kawaguchi T, Stahl EA, Kurreeman FA, Nishida N et al.. (2012) Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population. Nat Genet, 44 (5): 511-6. [PMID:22446963]

9. Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N. (2004) Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem, 279 (7): 5298-305. [PMID:14634025]

10. Osisami M, Ali W, Frohman MA. (2012) A role for phospholipase D3 in myotube formation. PLoS ONE, 7 (3): e33341. [PMID:22428023]

11. Petersen G, Hansen HS. (1999) N-acylphosphatidylethanolamine-hydrolysing phospholipase D lacks the ability to transphosphatidylate. FEBS Lett, 455 (1-2): 41-4. [PMID:10428468]

12. Preininger AM, Henage LG, Oldham WM, Yoon EJ, Hamm HE, Brown HA. (2006) Direct modulation of phospholipase D activity by Gbetagamma. Mol Pharmacol, 70 (1): 311-8. [PMID:16638972]

13. Randall RW, Bonser RW, Thompson NT, Garland LG. (1990) A novel and sensitive assay for phospholipase D in intact cells. FEBS Lett, 264 (1): 87-90. [PMID:2186929]

14. Sarri E, Pardo R, Fensome-Green A, Cockcroft S. (2003) Endogenous phospholipase D2 localizes to the plasma membrane of RBL-2H3 mast cells and can be distinguished from ADP ribosylation factor-stimulated phospholipase D1 activity by its specific sensitivity to oleic acid. Biochem J, 369 (Pt 2): 319-29. [PMID:12374567]

15. Scott SA, Selvy PE, Buck JR, Cho HP, Criswell TL, Thomas AL, Armstrong MD, Arteaga CL, Lindsley CW, Brown HA. (2009) Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness. Nat Chem Biol, 5 (2): 108-17. [PMID:19136975]

16. Suzuki T, Ikari K, Yano K, Inoue E, Toyama Y, Taniguchi A, Yamanaka H, Momohara S. (2013) PADI4 and HLA-DRB1 are genetic risks for radiographic progression in RA patients, independent of ACPA status: results from the IORRA cohort study. PLoS ONE, 8 (4): e61045. [PMID:23577190]

17. Terao C, Ohmura K, Kawaguchi Y, Nishimoto T, Kawasaki A, Takehara K, Furukawa H, Kochi Y, Ota Y, Ikari K et al.. (2013) PLD4 as a novel susceptibility gene for systemic sclerosis in a Japanese population. Arthritis Rheum, 65 (2): 472-80. [PMID:23124809]

18. Wang Q, Zhu H, Sun X, Zhang C, Ma S, Jin Y, Fu J, Liu C, Peng J, Wang R et al.. (2025) Loss-of-function mutations in PLD4 lead to systemic lupus erythematosus. Nature, 647 (8089): 498-505. [PMID:40931063]

19. Yoshikawa F, Banno Y, Otani Y, Yamaguchi Y, Nagakura-Takagi Y, Morita N, Sato Y, Saruta C, Nishibe H, Sadakata T et al.. (2010) Phospholipase D family member 4, a transmembrane glycoprotein with no phospholipase D activity, expression in spleen and early postnatal microglia. PLoS ONE, 5 (11): e13932. [PMID:21085684]