Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

E-NTPDase Family

  • Jean SévignyEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_197


Historical Background

Nucleoside triphosphate diphosphohydrolases (NTPDases), originally ATP diphosphohydrolases (ATPDases) with the common name apyrase, are by definition enzymes which split the γ- and β-phosphate residues of triphospho- and diphosphonucleosides such as ATP and ADP, respectively. Before the cloning of the gene, the common name “apyrase” was generally used for enzymes that exhibit this activity in plants and invertebrates while the terms ecto-ATPase and ATP diphosphohydrolase (ATPDase) were rather used in vertebrates (Beaudoin et al. 1996). Shortly after cloning the first gene encoding such an enzyme, the nomenclature was unified in mammals to NTPDase, which better reflects the ability of these enzymes to convert not only ATP and ADP but also other triphospho- and diphosphonucleosides (Zimmermann et al. 1999...

This is a preview of subscription content, log in to check access.


  1. al-Rashida M, Iqbal J. Therapeutic potentials of ecto-nucleoside triphosphate diphosphohydrolase, ecto-nucleotide pyrophosphatase/phosphodiesterase, ecto-5′-nucleotidase, and alkaline phosphatase inhibitors. Med Res Rev. 2014;34:703–43.  https://doi.org/10.1002/med.21302.CrossRefPubMedGoogle Scholar
  2. Beaudoin AR, Sévigny J, Picher M. ATP-diphosphohydrolases, apyrases, and nucleotide phosphohydrolases: biochemical properties and functions. In: Lee AG, editor. ATPases. Greenwich: JAI Press Inc; 1996. p. 369–401.CrossRefGoogle Scholar
  3. Bigonnesse F, Lévesque SA, Kukulski F, Lecka J, Robson SC, Fernandes MJG, et al. Cloning and characterization of mouse nucleoside triphosphate diphosphohydrolase-8. Biochemistry. 2004;43:5511–9.CrossRefPubMedGoogle Scholar
  4. Deaglio S, Robson SC. Ectonucleotidases as regulators of purinergic signaling in thrombosis, inflammation, and immunity. Adv Pharmacol. 2011;61:301–32.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Enjyoji K, Sévigny J, Lin Y, Frenette PS, Christie PD, Esch II JSA, et al. Targeted disruption of CD39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nat Med. 1999;5:1010–7.CrossRefPubMedGoogle Scholar
  6. Friedman DJ, Kunzli BM, AR YI, Sévigny J, PO B, Enjyoji K, et al. From the Cover: CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease. Proc Natl Acad Sci U S A. 2009;106:16788–93.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Gampe K, Haverkamp S, Robson SC, Gachet C, Huser L, Acker-Palmer A, et al. NTPDase2 and the P2Y1 receptor are not required for mammalian eye formation. Purinergic Signalling. 2015;11:155–60.CrossRefPubMedGoogle Scholar
  8. Grinthal A, Guidotti G. CD39, NTPDase 1, is attached to the plasma membrane by two transmembrane domains. Why? Purinergic Signalling. 2006;2:391–8.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Ivanenkov VV, Meller J, Kirley TL. Characterization of disulfide bonds in human nucleoside triphosphate diphosphohydrolase 3 (NTPDase3): implications for NTPDase structural modeling. Biochemistry. 2005;44:8998–9012.CrossRefPubMedGoogle Scholar
  10. Kaczmarek E, Koziak K, Sévigny J, Siegel JB, Anrather J, Beaudoin AR, et al. Identification and characterization of CD39 vascular ATP diphosphohydrolase. J Biol Chem. 1996;271:33116–22.CrossRefPubMedGoogle Scholar
  11. Kauffenstein G, Pelletier J, Lavoie EG, Kukulski F, Martín-Satué M, Dufresne SS, et al. Nucleoside triphosphate diphosphohydrolase-1 ectonucleotidase is required for normal vas deferens contraction and male fertility through maintaining P2X1 receptor function. J Biol Chem. 2014;289:28629–39.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Kegel B, Braun N, Heine P, Maliszewski CR, Zimmermann H. An ecto-ATPase and an ecto-ATP diphosphohydrolase are expressed in rat brain. Neuropharmacol. 1997;36:1189–200.CrossRefGoogle Scholar
  13. Kirley TL. Complementary DNA cloning and sequencing of the chicken muscle ecto-ATPase: homology with the lymphoid cell activation antigen CD39. J Biol Chem. 1997;272:1076–81.CrossRefPubMedGoogle Scholar
  14. Kittel A, Kaczmarek E, Sévigny J, Lengyel K, Csizmadia E, Robson SC. CD39 as a caveolar-associated ectonucleotidase. Biochem Biophys Res Commun. 1999;262:596–9.CrossRefPubMedGoogle Scholar
  15. Knowles AF. The GDA1_CD39 superfamily: NTPDases with diverse functions. Purinergic Signalling. 2011;7:21–45.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Koziak K, Kaczmarek E, Kittel A, Sévigny J, Blusztajn JK, Esch II JSA, et al. Palmitoylation targets CD39/endothelial ATP diphosphohydrolase to caveolae. J Biol Chem. 2000;275:2057–62.CrossRefPubMedGoogle Scholar
  17. Kukulski F, Lévesque SA, Lavoie EG, Lecka J, Bigonnesse F, Knowles AF, et al. Comparative hydrolysis of P2 receptor agonists by NTPDases 1, 2, 3 and 8. Purinergic Signalling. 2005;1:193–204.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Kukulski F, Lévesque SA, Sévigny J. Impact of ectoenzymes on P2 and P1 receptor signaling. Adv Pharmacol. 2011;61:263–99.PubMedCrossRefGoogle Scholar
  19. Massé K, Bhamra S, Eason R, Dale N, Jones EA. Purine-mediated signalling triggers eye development. Nature. 2007;449:1058–62.CrossRefPubMedGoogle Scholar
  20. Mizumoto N, Kumamoto T, Robson SC, Sévigny J, Matsue H, Enjyoji K, et al. CD39 is the dominant Langerhans cell-associated ecto-NTPDase: modulatory roles in inflammation and immune responsiveness. Nat Med. 2002;8:358–65.CrossRefPubMedGoogle Scholar
  21. Plesner L. Ecto-ATPases: identities and functions. Int Rev Cytol. 1995;158:141–214.CrossRefPubMedGoogle Scholar
  22. Robson SC, Sévigny J, Zimmermann H. The E-NTPDase family of ectonucleotidases: structure function relationships and pathophysiological significance. Purinergic Signalling. 2006;2:409–30.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Sévigny J, Sundberg C, Braun N, Guckelberger O, Csizmadia E, Qawi I, et al. Differential catalytic properties and vascular topography of murine nucleoside triphosphate diphosphohydrolase 1 (NTPDase1) and NTPDase2 have implications for thromboregulation. Blood. 2002;99:2801–9.CrossRefPubMedGoogle Scholar
  24. Smith TM, Kirley TL. Cloning, sequencing, and expression of a human brain ecto-apyrase related to both the ecto-ATPases and CD39 ecto-apyrases. BBA-Protein Struct M. 1998;1386:65–78.CrossRefGoogle Scholar
  25. Takenaka MC, Robson S, Quintana FJ. Regulation of the T cell response by CD39. Trends Immunol. 2016;37:427–39.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Wang T-F, Guidotti G. CD39 is an ecto-(Ca2+, Mg2+)-apyrase. J Biol Chem. 1996;271:9898–901.CrossRefPubMedGoogle Scholar
  27. Yegutkin GG. Enzymes involved in metabolism of extracellular nucleotides and nucleosides: functional implications and measurement of activities. Crit Rev Biochem Mol Biol. 2014;49:473–97.CrossRefPubMedGoogle Scholar
  28. Yegutkin GG. Nucleotide- and nucleoside-converting ectoenzymes: important modulators of purinergic signalling cascade. Biochim Biophys Acta. 2008;1783:673–94.CrossRefPubMedGoogle Scholar
  29. Zebisch M, Strater N. Structural insight into signal conversion and inactivation by NTPDase2 in purinergic signaling. Proc Natl Acad Sci U S A. 2008;105:6882–7.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Zimmermann H, Beaudoin AR, Bollen M, Goding JW, Guidotti G, Kirley TL, et al., editors. Proposed nomenclature for two novel nucleotide hydrolyzing enzyme families expressed on the cell surface. Ecto-ATPases and Related Ectonucleotidases; 1999 2000; Diepenbeek: Shaker Publishing BV, Maastricht.Google Scholar
  31. Zimmermann H, Zebisch M, Strater N. Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signalling. 2012;8:437–502.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Microbiology-Infectiology and Immunology, Faculty of MedicineCentre de Recherche du CHU de Québec - Université LavalQuebec CityCanada