Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Neutral Ceramidase

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101723


Historical Background

Ceramidase (CDase) is an enzyme that hydrolyzes the N-acyl linkage between a fatty acid and a sphingoid base in ceramide (Cer) and is widely distributed from bacteria to mammals. Cer comprises the hydrophobic portion of complex sphingolipids including sphingomyelin and glycosphingolipids. The most abundant sphingoid base in mammalian tissues is sphingosine (Sph), which has a trans-double bond between the C4 and C5 positions, and Sph can be phosphorylated by Sph kinases and converted to Sph 1-phosphate (S1P). Cer, Sph, and S1P have been shown to function as lipid signaling molecules that regulate various signal transduction systems. Sph cannot be synthesized via the de novo sphingolipid biosynthesis pathway; that is, the formation of the C4–C5 trans-double bond by dihydroceramide desaturase, DES1, occurs after N-acylation of dihydrosphingosine by Cer synthases, and...
This is a preview of subscription content, log in to check access.


  1. Airola MV, Allen WJ, Pulkoski-Gross MJ, Obeid LM, Rizzo RC, Hannun YA. Structural basis for ceramide recognition and hydrolysis by human neutral ceramidase. Structure. 2015;23:1482–91.PubMedPubMedCentralCrossRefGoogle Scholar
  2. El Bawab S, Birbes H, Roddy P, Szulc ZM, Bielawska A, Hannun YA. Biochemical characterization of the reverse activity of rat brain ceramidase. A CoA-independent and fumonisin B1-insensitive ceramide synthase. J Biol Chem. 2001;276:16758–66.CrossRefPubMedGoogle Scholar
  3. Garcia-Barros M, Coant N, Kawamori T, Wada M, Snider AJ, Truman JP, Wu BX, Furuya H, Clarke CJ, Bialkowska AB, Ghaleb A, Yang VW, Obeid LM, Hannun YA. Role of neutral ceramidase in colon cancer. FASEB J. 2016;30:4159–71.  https://doi.org/10.1096/fj.201600611R.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Gatt S. Enzymic hydrolysis and synthesis of ceramides. J Biol Chem. 1963;238:3131–3.PubMedGoogle Scholar
  5. Inoue T, Okino N, Kakuta Y, Hijikata A, Okano H, Goda HM, Tani M, Sueyoshi N, Kambayashi K, Matsumura H, Kai Y, Ito M. Mechanistic insights into the hydrolysis and synthesis of ceramide by neutral ceramidase. J Biol Chem. 2009;284:9566–77.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Ito M, Okino N, Tani M. New insight into the structure, reaction mechanism, and biological functions of neutral ceramidase. Biochim Biophys Acta. 2014;1841:682–91.CrossRefPubMedGoogle Scholar
  7. Kono M, Dreier JL, Ellis JM, Allende ML, Kalkofen DN, Sanders KM, Bielawski J, Bielawska A, Hannun YA, Proia RL. Neutral ceramidase encoded by the Asah2 gene is essential for the intestinal degradation of sphingolipids. J Biol Chem. 2006;281:7324–31.CrossRefPubMedGoogle Scholar
  8. Mitsutake S, Tani M, Okino N, Mori K, Ichinose S, Omori A, Iida H, Nakamura T, Ito M. Purification, characterization, molecular cloning, and subcellular distribution of neutral ceramidase of rat kidney. J Biol Chem. 2001;276:26249–59.CrossRefPubMedGoogle Scholar
  9. Novgorodov SA, Riley CL, Yu J, Borg KT, Hannun YA, Proia RL, Kindy MS, Gudz TI. Essential roles of neutral ceramidase and sphingosine in mitochondrial dysfunction due to traumatic brain injury. J Biol Chem. 2014;289:13142–54.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Okino N, Ichinose S, Omori A, Imayama S, Nakamura T, Ito M. Molecular cloning, sequencing, and expression of the gene encoding alkaline ceramidase from Pseudomonas aeruginosa. Cloning of a ceramidase homologue from Mycobacterium tuberculosis. J Biol Chem. 1999;274:36616–22.CrossRefPubMedGoogle Scholar
  11. Okino N, Mori K, Ito M. Genomic structure and promoter analysis of the mouse neutral ceramidase gene. Biochem Biophys Res Commun. 2002;299:160–6.CrossRefPubMedGoogle Scholar
  12. Snider AJ, Wu BX, Jenkins RW, Sticca JA, Kawamori T, Hannun YA, Obeid LM. Loss of neutral ceramidase increases inflammation in a mouse model of inflammatory bowel disease. Prostaglandins Other Lipid Mediat. 2012;99:124–30.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Sundaram K, Mather AR, Marimuthu S, Shah PP, Snider AJ, Obeid LM, Hannun YA, Beverly LJ, Siskind LJ. Loss of neutral ceramidase protects cells from nutrient- and energy -deprivation-induced cell death. Biochem J. 2016;473:743–55.PubMedCrossRefGoogle Scholar
  14. Tani M, Ito M, Igarashi Y. Ceramide/sphingosine/sphingosine 1-phosphate metabolism on the cell surface and in the extracellular space. Cell Signal. 2007;19:229–37.CrossRefPubMedGoogle Scholar
  15. Tani M, Okino N, Mitsutake S, Tanigawa T, Izu H, Ito M. Purification and characterization of a neutral ceramidase from mouse liver. A single protein catalyzes the reversible reaction in which ceramide is both hydrolyzed and synthesized. J Biol Chem. 2000a;275:3462–8.CrossRefPubMedGoogle Scholar
  16. Tani M, Okino N, Mori K, Tanigawa T, Izu H, Ito M. Molecular cloning of the full-length cDNA encoding mouse neutral ceramidase. A novel but highly conserved gene family of neutral/alkaline ceramidases. J Biol Chem. 2000b;275:11229–34.CrossRefPubMedGoogle Scholar
  17. Uchida Y, Houben E, Park K, Douangpanya S, Lee YM, Wu BX, Hannun YA, Radin NS, Elias PM, Holleran WM. Hydrolytic pathway protects against ceramide-induced apoptosis in keratinocytes exposed to UVB. J Invest Dermatol. 2010;130:2472–80.CrossRefPubMedGoogle Scholar
  18. Yavin E, Gatt S. Enzymatic hydrolysis of sphingolipids. 8. Further purification and properties of rat brain ceramidase. Biochemistry. 1969;8:1692–8.CrossRefPubMedGoogle Scholar
  19. Yoshimura Y, Tani M, Okino N, Iida H, Ito M. Molecular cloning and functional analysis of zebrafish neutral ceramidase. J Biol Chem. 2004;279:44012–22.CrossRefPubMedGoogle Scholar
  20. Zhu Q, Jin JF, Shan XH, Liu CP, Mao XD, Xu KF, Liu C. Chronic activation of neutral ceramidase protects beta-cells against cytokine-induced apoptosis. Acta Pharmacol Sin. 2008;29:593–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Chemistry, Faculty of SciencesKyushu UniversityFukuokaJapan
  2. 2.Department of Bioscience and BiotechnologyGraduate School of Bioresource and Bioenvironmental Sciences, Kyushu UniversityFukuokaJapan