Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Sphingomyelinase, Acidic

  • Nadine Beckmann
  • Erich GulbinsEmail author
  • Katrin Anne Becker
  • Alexander Carpinteiro
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101873


Historical Background

Acid sphingomyelinase (ASM, Enzyme Commission classification number is one of the hydrolases that catalyze the breakdown of sphingomyelin to phosphorylcholine and the signaling molecule ceramide. Its importance was first realized when ASM deficiency was identified as the cause of the lysosomal storage disorder Niemann-Pick disease types A and B. Originally, because of its acidic pH optimum in vitro (pH 4,5–5,0), ASM was assumed to be a purely lysosomal enzyme. Further studies have since revealed that ASM is not restricted to the lysosomes, but can also translocate to and function at the extracellular cell surface (Grassmé et al. 2001). This is important for ASM-mediated signaling, which typically occurs through the generation of ceramide-enriched plasma membrane platforms. This mechanism was first demonstrated for CD95-DISC formation (Grassmé et al. 2001...

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  1. Beckmann N, Sharma D, Gulbins E, Becker KA, Edelmann B. Inhibition of acid sphingomyelinase by tricyclic antidepressants and analogons. Front Physiol. 2014;5:331. doi:10.3389/fphys.2014.00331.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Carpinteiro A, Becker KA, Japtok L, Hessler G, Keitsch S, Požgajovà M, Schmid KW, Adams C, Müller S, Kleuser B, Edwards MJ, Grasmmé H, Helfrich I, Gulbins E. Regulation of hematogenous tumor metastasis by acid sphingomyelinase. EMBO Mol Med. 2015;7(6):714–34. doi:10.15252/emmm.201404571.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Edelmann B, Bertsch U, Tchikov V, Winoto-Morbach S, Perrotta C, Jakob M, Adam-Klages S, Kabelitz D, Schütze S. Caspase-8 and caspase-7 sequentially mediate proteolytic activation of acid sphingomyelinase in TNF-R1 receptosomes. EMBO J. 2011;30(2):379–94. doi:10.1038/emboj.2010.326.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Gorelik A, Illes K, Heinz LX, Superti-Furga G, Nagar B. Crystal structure of mammalian acid sphingomyelinase. Nat Commun. 2016;7:12196. doi:10.1038/ncomms12196.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Grassmé H, Gulbins E, Brenner B, Ferlinz K, Sandhoff K, Harzer K, Lang F, Meyer TF. Acidic sphingomyelinase mediates entry of N. gonorrhoeae into nonphagocytic cells. Cell. 1997;91(5):605–15. doi:10.1016/S0092-8674(00)80448-1.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Grassmé H, Jekle A, Riehle A, Schwarz H, Berger J, Sandhoff K, Kolesnick R, Gulbins E. CD95 signaling via ceramide-rich membrane rafts. J Biol Chem. 2001;276(23):20589–96. doi:10.1074/jbc.M101207200.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Grassmé H, Riethmüller J, Gulbins E. Biological aspects of ceramide-enriched membrane domains. Prog Lipid Res. 2007;46(3–4):161–70. doi:10.1016/j.plipres.2007.03.002.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Gulbins E, Palmada M, Reichel M, Lüth A, Böhmer C, Amato D, Müller CP, Tischbirek CH, Groemer TW, Tabatabai G, Becker KA, Tripal P, Staedter S, Ackermann TF, van Brederode J, Alzheimer C, Weller M, Lang UE, Kleuser B, Grassmé H, Kornhuber J. Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs. Nat Med. 2013;19(7):934–8. doi:10.1038/nm.3214.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Hurwitz R, Ferlinz K, Vielhaber G, Moczall H, Sandhoff K. Processing of human acid sphingomyelinase in Normal and I-cell fibroblasts. J Biol Chem. 1994;269(7):5440–5.PubMedPubMedCentralGoogle Scholar
  10. Kölzer M, Arenz C, Ferlinz K, Werth N, Schulze H, Klingenstein R, Sandhoff K. Phosphatidylinositol-3,5-bisphosphate is a potent selective inhibitor of acid sphingomyelinase. Biol Chem. 2003;384(9):1293–8. doi:10.1515/BC.2003.144.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Kornhuber J, Tripal P, Reichel M, Mühle C, Rhein C, Muehlbacher M, Groemer TW, Gulbins E. Functional inhibitors of acid sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications. Cell Physiol Biochem. 2010;26(1):9–20. doi:10.1159/000315101.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Kornhuber J, Rhein C, Müller CP, Mühle C. Secretory sphingomyelinase in health and disease. Biol Chem. 2015;396(6–7):707–36. doi:10.1515/hsz-2015-0109.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Perrotta C, Bizzozero L, Cazzato D, Morlacchi S, Assi E, Simbari F, Zhang Y, Gulbins E, Bassi MT, Rosa P, Clementi E. Syntaxin 4 is required for acid sphingomyelinase activity and apoptotic function. J Biol Chem. 2010;285(51):40240–51. doi:10.1074/jbc.M110.139287.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Qiu H, Edmunds T, Baker-Malcolm J, Karey KP, Estes S, Schwarz C, Hughes H, Van Patten SM. Activation of human acid sphingomyelinase through modification or deletion of C-terminal cysteine. J Biol Chem. 2003;278(35):32744–52. doi:10.1074/jbc.M303022200.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Rhein C, Tripal P, Seebahn A, Konrad A, Kramer M, Nagel C, Kemper J, Bode J, Mühle C, Gulbins E, Reichel M, Becker CM, Kornhuber J. Functional implications of novel human acid sphingomyelinase splice variants. PLoS One. 2012;7(4):e35467. doi:10.1371/journal.pone.0035467.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Schissel SL, Keesler GA, Schuchman EH, Williams KJ, Tabas I. The cellular trafficking and zinc dependence of secretory and lysosomal sphingomyelinase, two products of the acid sphingomyelinase gene. J Biol Chem. 1998;273(29):18250–9. doi:10.1074/jbc.273.18250.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Schuchman EH, Suchi M, Takahashi T, Sandhoff K, Desnick RJ. Human acid sphingomyelinase. Isolation, nucleotide sequence and expression of the full-length and alternatively spliced cDNAS. J Biol Biochem. 1991;266(13):8531–9.Google Scholar
  18. Siskind LJ, Colombini M. The lipids C2- and C16-ceramide form large stable channels. Implications for apoptosis. J Biol Chem. 2000;275(49):38640–4. doi:10.1074/jpc.C000587200.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Teichgräber V, Ulrich M, Endlich N, Riethmüller J, Wilker B, De Oliveira-Munding CC, van Heeckeren AM, Barr ML, von Kürthy G, Schmid KW, Wellter M, Tümmler B, Lang F, Grassmé H, Döring G, Gulbins E. Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis. Nat Med. 2008;14(4):382–91. doi:10.1038/nm1748.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Xiong ZJ, Huang J, Poda G, Pomès R, Privé GG. Structure of human acid sphingomyelinase reveals the role of the saposin domain in activating substrate hydrolysis. J Mol Biol. 2016; pii: S0022-2836(16)30220-0. doi:10.1016/j.jmb.2016.06.012.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  • Nadine Beckmann
    • 1
  • Erich Gulbins
    • 1
    • 2
    Email author
  • Katrin Anne Becker
    • 1
  • Alexander Carpinteiro
    • 1
  1. 1.Department of Molecular BiologyUniversity of Duisburg-EssenEssenGermany
  2. 2.Department of SurgeryUniversity of CincinnatiCincinnatiUSA