An Overview of Sphingolipid Metabolism: From Synthesis to Breakdown

  • Christopher R. Gault
  • Lina M. Obeid
  • Yusuf A. Hannun
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 688)


Sphingolipids constitute a class of lipids defined by their eighteen carbon amino-alcohol backbones which are synthesized in the ER from nonsphingolipid precursors. Modification of this basic structure is what gives rise to the vast family of sphingolipids that play significant roles in membrane biology and provide many bioactive metabolites that regulate cell function. Despite the diversity of structure and function of sphingolipids, their creation and destruction are governed by common synthetic and catabolic pathways. In this regard, sphingolipid metabolism can be imagined as an array of interconnected networks that diverge from a single common entry point and converge into a single common breakdown pathway.

In their simplest forms, sphingosine, phytosphingosine and dihydrosphingosine serve as the backbones upon which further complexity is achieved. For example, phosphorylation of the C1 hydroxyl group yields the final breakdown products and/or the important signaling molecules sphingosine-1-phosphate, phytosphingosine-1-phosphate and dihydrosphingosine-1-phosphate, respectively. On the other hand, acylation of sphingosine, phytosphingosine, or dihydrosphingosine with one of several possible acyl CoA molecules through the action of distinct ceramide synthases produces the molecules defined as ceramide, phytoceramide, or dihydroceramide. Ceramide, due to the differing acyl CoAs that can be used to produce it, is technically a class of molecules rather than a single molecule and therefore may have different biological functions depending on the acyl chain it is composed of.

At the apex of complexity is the group of lipids known as glycosphingolipids (GSL) which contain dozens of different sphingolipid species differing by both the order and type of sugar residues attached to their headgroups. Since these molecules are produced from ceramide precursors, they too may have differences in their acyl chain composition, revealing an additional layer of variation. The glycosphingolipids are divided broadly into two categories: glucosphingolipids and galactosphingolipids. The glucosphingolipids depend initially on the enzyme glucosylceramide synthase (GCS) which attaches glucose as the first residue to the C1 hydroxyl position. Galactosphingolipids, on the other hand, are generated from galactosylceramide synthase (GalCerS), an evolutionarily dissimilar enzyme from GCS. Glycosphingolipids are further divided based upon further modification by various glycosyltransferases which increases the potential variation in lipid species by several fold. Far more abundant are the sphingomyelin species which are produced in parallel with glycosphingolipids, however they are defined by a phosphocholine headgroup rather than the addition of sugar residues. Although sphingomyelin species all share a common headgroup, they too are produced from a variety of ceramide species and therefore can have differing acyl chains attached to their C-2 amino groups. Whether or not the differing acyl chain lengths in SMs dictate unique functions or important biophysical distinctions has not yet been established. Understanding the function of all the existing glycosphingolipids and sphingomyelin species will be a major undertaking in the future since the tools to study and measure these species are only beginning to be developed (see Fig 1 for an illustrated depiction of the various sphingolipid structures).

The simple sphingolipids serve both as the precursors and the breakdown products of the more complex ones. Importantly, in recent decades, these simple sphingolipids have gained attention for having significant signaling and regulatory roles within cells. In addition, many tools have emerged to measure the levels of simple sphingolipids and therefore have become the focus of even more intense study in recent years. With this thought in mind, this chapter will pay tribute to the complex sphingolipids, but focus on the regulation of simple sphingolipid metabolism.
Figure 1.

Simple and complex sphingolipid structures. Structures shown: (A) 3-Ketodihydrosphingosine, (B) Dihydrosphingosine, (C) Phytosphingosine, (D) Sphingosine, (E) Sphingosine-1-Phosphate, (F) Dihydroceramide: Boxed region shows variable acyl chain, (G) Ceramide, (H) Complex Sphingolipids: Sphingomyelin shown with phosphocholine R group. Substitute R for glucose=Glucosylceramide, Substitute R for galactose=Galactosylceramide.


Sphingosine Kinase Acyl Chain Length Acid Ceramidase Ceramide Species Serine Palmitoyltransferase 


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  1. 1.
    Mandon EC, Ehses I, Rother J et al. Subcellular localization and membrane topology of serine palmitoyltransferase, 3-dehydrosphinganine reductase and sphinganine N-acyltransferase in mouse liver. J Biol Chem 1992; 267(16):11144–8.PubMedGoogle Scholar
  2. 2.
    Hornemann T, Richard S, Rütti MF et al. Cloning and initial characterization of a new subunit for mammalian serine-palmitoyltransferase. J Biol Chem 2006; 281(49):37275–81.PubMedCrossRefGoogle Scholar
  3. 3.
    Yasuda S, Nishijima M, Hanada K. Localization, topology and function of the LCB1 subunit of serine palmitoyltransferase in mammalian cells. J Biol Chem 2003; 278(6):4176–83.PubMedCrossRefGoogle Scholar
  4. 4.
    Hojjati MR, Li Z, Jiang XC. Serine palmitoyl-CoA transferase (SPT) deficiency and sphingolipid levels in mice. Biochim Biophys Acta 2005; 1737(1):44–51.PubMedGoogle Scholar
  5. 5.
    Gable K et al. Tsc3p is an 80-amino acid protein associated with serine palmitoyltransferase and required for optimal enzyme activity. J Biol Chem 2000; 275(11):7597–603.PubMedCrossRefGoogle Scholar
  6. 6.
    Hanada K. Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism. Biochim Biophys Acta 2003; 1632(1–3):16–30.PubMedGoogle Scholar
  7. 7.
    Merrill AH Jr. Characterization of serine palmitoyltransferase activity in Chinese hamster ovary cells. Biochim Biophys Acta 1983; 754(3):284–91.PubMedGoogle Scholar
  8. 8.
    Dawkins JL et al. Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet 2001; 27(3):309–12.PubMedCrossRefGoogle Scholar
  9. 9.
    Spring PJ, Kok C, Nicholson GA et al. Autosomal dominant hereditary sensory neuropathy with chronic cough and gastro-oesophageal reflux: clinical features in two families linked to chromosome 3p22-p24. Brain 2005; 128(Pt 12):2797–810.PubMedCrossRefGoogle Scholar
  10. 10.
    Lindahl AJ, Lhatoo SD, Campbell MJ et al. Late-onset hereditary sensory neuropathy type I due to SPTLC1 mutation: autopsy findings. Clin Neurol Neurosurg 2006; 108(8):780–3.PubMedCrossRefGoogle Scholar
  11. 11.
    Bejaoui K et al. SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat Genet 2001; 27(3):261–2.PubMedCrossRefGoogle Scholar
  12. 12.
    McCampbell A et al. Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy. Hum Mol Genet 2005; 14(22):3507–21.PubMedCrossRefGoogle Scholar
  13. 13.
    Bejaoui K, Wu C, Scheffler MD et al. Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis. J Clin Invest 2002; 110(9):1301–8.PubMedGoogle Scholar
  14. 14.
    Dawkins JL, Brahmbhatt S, Auer-Grumbach M et al. Exclusion of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) as a common cause for hereditary sensory neuropathy. Neuromuscul Disord 2002; 12(7–8):656–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Beeler T, Bacikova D, Gable K et al. The Saccharomyces cerevisiae TSC10/YBR265w gene encoding 3-ketosphinganine reductase is identified in a screen for temperature-sensitive suppressors of the Ca2+-sensitive csg2Delta mutant. J Biol Chem 1998; 273(46):30688–94.PubMedCrossRefGoogle Scholar
  16. 16.
    Kihara A, Igarashi Y. FVT-1 is a mammalian 3-ketodihydrosphingosine reductase with an active site that faces the cytosolic side of the endoplasmic reticulum membrane. J Biol Chem 2004; 279(47):49243–50.PubMedCrossRefGoogle Scholar
  17. 17.
    Krebs S, Medugorac I, Röther S et al. A missense mutation in the 3-ketodihydrosphingosine reductase FVT1 as candidate causal mutation for bovine spinal muscular atrophy. Proc Natl Acad Sci USA 2007; 104(16):6746–51.PubMedCrossRefGoogle Scholar
  18. 18.
    Pewzner-Jung Y, Ben-Dor S, Futerman AH. When do Lasses (longevity assurance genes) become CerS (ceramide synthases)? Insights into the regulation of ceramide synthesis. J Biol Chem 2006; 281(35):25001–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Lahiri S, Lee H, Mesicek J et al. Kinetic characterization of mammalian ceramide synthases: determination of K(m) values towards sphinganine. FEBS Lett 2007; 581(27):5289–94.PubMedCrossRefGoogle Scholar
  20. 20.
    Venkataraman K, Riebeling C, Bodennec J et al. Upstream of growth and differentiation factor 1 (uog1), a mammalian homolog of the yeast longevity assurance gene 1 (LAG1), regulates N-stearoyl-sphinganine (C18-(dihydro)ceramide) synthesis in a fumonisin B1-independent manner in mammalian cells. J Biol Chem 2002; 277(38):35642–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Laviad EL, Albee L, Pankova-Kholmyansky I et al. Characterization of ceramide synthase 2: tissue distribution, substrate specificity and inhibition by sphingosine-1-phosphate. J Biol Chem 2008; 283(9):5677–84.PubMedCrossRefGoogle Scholar
  22. 22.
    Riebeling C, Allegood JC, Wang E et al. Two mammalian longevity assurance gene (LAG1) family members, trh1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors. J Biol Chem 2003; 278(44):43452–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Mizutani Y, Kihara A, Igarashi Y. Mammalian Lass6 and its related family members regulate synthesis of specific ceramides. Biochem J 2005; 390(Pt 1):263–71.PubMedGoogle Scholar
  24. 24.
    Mizutani Y, Kihara A, Igarashi Y. LASS3 (longevity assurance homologue 3) is a mainly testis-specific (dihydro)ceramide synthase with relatively broad substrate specificity. Biochem J 2006; 398(3):531–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Mizutani Y et al. 2-Hydroxy-ceramide synthesis by ceramide synthase family: enzymatic basis for the preference of FA chain length. J Lipid Res 2008; 49(11):2356–64.PubMedCrossRefGoogle Scholar
  26. 26.
    Bose R, Verheij M, Haimovitz-Friedman A et al. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 1995; 82(3):405–14.PubMedCrossRefGoogle Scholar
  27. 27.
    Cadena DL, Kurten RC, Gill GN. The product of the MLD gene is a member of the membrane fatty acid desaturase family: overexpression of MLD inhibits EGF receptor biosynthesis. Biochemistry 1997; 36(23):6960–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Geeraert L, Mannaerts GP, van Veldhoven PP. Conversion of dihydroceramide into ceramide: involvement of a desaturase. Biochem J 1997; 327(Pt 1):125–32.PubMedGoogle Scholar
  29. 29.
    Michel C, van Echten-Deckert G, Rother J et al. Characterization of ceramide synthesis. A dihydroceramide desaturase introduces the 4,5-trans-double bond of sphingosine at the level of dihydroceramide. J Biol Chem 1997; 272(36):22432–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Savile CK, Fabrias G, Buist PH. Dihydroceramide delta(4) desaturase initiates substrate oxidation at C-4. J Am Chem Soc 2001; 123(19):4382–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Ternes P, Franke S, Zähringer U et al. Identification and characterization of a sphingolipid delta 4-desaturase family. J Biol Chem 2002; 277(28):25512–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Beauchamp E, Goenaga D, Le Bloc’h J et al. Myristic acid increases the activity of dihydroceramide Delta4-desaturase 1 through its N-terminal myristoylation. Biochimie 2007; 89(12):1553–61.PubMedCrossRefGoogle Scholar
  33. 33.
    Mizutani Y, Kihara A, Igarashi Y. Identification of the human sphingolipid C4-hydroxylase, hDES2 and its up-regulation during keratinocyte differentiation. FEBS Lett 2004; 563(1–3):93–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Omae F, Miyazaki M, Enomoto A et al. DES2 protein is responsible for phytoceramide biosynthesis in the mouse small intestine. Biochem J 2004; 379(Pt 3):687–95.PubMedCrossRefGoogle Scholar
  35. 35.
    Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 2008; 9(2):139–50.PubMedCrossRefGoogle Scholar
  36. 36.
    Holland WL, Brozinick JT, Wang LP et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-and obesity-induced insulin resistance. Cell Metab 2007; 5(3):167–79.PubMedCrossRefGoogle Scholar
  37. 37.
    Hanada K, Kumagai K, Tomishige N et al. CERT and intracellular trafficking of ceramide. Biochim Biophys Acta 2007; 1771(6):644–53.PubMedGoogle Scholar
  38. 38.
    Kumagai K, Kawano M, Shinkai-Ouchi F et al. Interorganelle trafficking of ceramide is regulated by phosphorylation-dependent cooperativity between the PH and START domains of CERT. J Biol Chem 2007; 282(24):17758–66.PubMedCrossRefGoogle Scholar
  39. 39.
    Charruyer A, Bell SM, Kawano M et al. Decreased ceramide transport protein (CERT) function alters sphingomyelin production following UVB irradiation. J Biol Chem 2008; 283(24):16682–92.PubMedCrossRefGoogle Scholar
  40. 40.
    Hanada K, Hara T, Fukasawa M et al. Mammalian cell mutants resistant to a sphingomyelin-directed cytolysin. Genetic and biochemical evidence for complex formation of the LCB1 protein with the LCB2 protein for serine palmitoyltransferase. J Biol Chem 1998; 273(50):33787–94.PubMedCrossRefGoogle Scholar
  41. 41.
    Hanada K, Kumagai K, Yasuda S et al. Molecular machinery for nonvesicular trafficking of ceramide. Nature 2003; 426(6968):803–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Kudo N, Kumagai K, Tomishige N et al. Structural basis for specific lipid recognition by CERT responsible for nonvesicular trafficking of ceramide. Proc Natl Acad Sci USA 2008; 105(2):488–93.PubMedCrossRefGoogle Scholar
  43. 43.
    Watson P, Stephens DJ. ER-to-Golgi transport: form and formation of vesicular and tubular carriers. Biochim Biophys Acta 2005; 1744(3):304–15.PubMedCrossRefGoogle Scholar
  44. 44.
    Stahl N, Jurevics H, Morell P et al. Isolation, characterization and expression of cDNA clones that encode rat UDP-galactose: ceramide galactosyltransferase. J Neurosci Res 1994; 38(2):234–42.PubMedCrossRefGoogle Scholar
  45. 45.
    Coetzee T, Li X, Fujita N et al. Molecular cloning, chromosomal mapping and characterization of the mouse UDP-galactose:ceramide galactosyltransferase gene. Genomics 1996; 35(1):215–22.PubMedCrossRefGoogle Scholar
  46. 46.
    Fujimoto H, Tadano-Aritomi K, Tokumasu A et al. Requirement of seminolipid in spermatogenesis revealed by UDP-galactose: Ceramide galactosyltransferase-deficient mice. J Biol Chem 2000; 275(30):22623–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Zoller I et al. Oligodendrocyte-specific ceramide galactosyltransferase (CGT) expression phenotypically rescues CGT-deficient mice and demonstrates that CGT activity does not limit brain galactosylceramide level. Glia 2005; 52(3):190–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Marcus J, Honigbaum S, Shroff S et al. Sulfatide is essential for the maintenance of CNS myelin and axon structure. Glia 2006; 53(4):372–81.PubMedCrossRefGoogle Scholar
  49. 49.
    Ichikawa S, Sakiyama H, Suzuki G et al. Expression cloning of a cDNA for human ceramide glucosyltransferase that catalyzes the first glycosylation step of glycosphingolipid synthesis. Proc Natl Acad Sci USA 1996; 93(10):4638–43.PubMedCrossRefGoogle Scholar
  50. 50.
    Jeckel D, Karrenbauer A, Burger KN et al. Glucosylceramide is synthesized at the cytosolic surface of various Golgi subfractions. J Cell Biol 1992; 117(2):259–67.PubMedCrossRefGoogle Scholar
  51. 51.
    D’Angelo G, Polishchuk E, Di Tullio G et al. Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature 2007; 449(7158):62–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Yamashita T, Wada R, Sasaki T et al. A vital role for glycosphingolipid synthesis during development and differentiation. Proc Natl Acad Sci USA 1999; 96(16):9142–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Jennemann R, Sandhoff R, Langbein L et al. Integrity and barrier function of the epidermis critically depend on glucosylceramide synthesis. J Biol Chem 2007; 282(5):3083–94.PubMedCrossRefGoogle Scholar
  54. 54.
    Jennemann R, Sandhoff R, Wang S et al. Cell-specific deletion of glucosylceramide synthase in brain leads to severe neural defects after birth. Proc Natl Acad Sci USA 2005; 102(35):12459–64.PubMedCrossRefGoogle Scholar
  55. 55.
    Yamashita T, Allende ML, Kalkofen DN et al. Conditional LoxP-flanked glucosylceramide synthase allele controlling glycosphingolipid synthesis. Genesis 2005; 43(4):175–80.PubMedCrossRefGoogle Scholar
  56. 56.
    Huitema K, van den Dikkenberg J, Brouwers JF et al. Identification of a family of animal sphingomyelin synthases. Embo J 2004; 23(1):33–44.PubMedCrossRefGoogle Scholar
  57. 57.
    Tafesse FG, Ternes P, Holthuis JC. The multigenic sphingomyelin synthase family. J Biol Chem 2006; 281(40):29421–5.PubMedCrossRefGoogle Scholar
  58. 58.
    Villani M, Subathra M, Im YB et al. Sphingomyelin synthases regulate production of diacylglycerol at the Golgi. Biochem J 2008; 414(1):31–41.PubMedCrossRefGoogle Scholar
  59. 59.
    Graf C, Niwa S, Müller M et al. Wild-type levels of ceramide and ceramide-1-phosphate in the retina of ceramide kinase-like-deficient mice. Biochem Biophys Res Commun 2008; 373(1):159–63.PubMedCrossRefGoogle Scholar
  60. 60.
    Wijesinghe DS, Massiello A, Subramanian P et al. Substrate specificity of human ceramide kinase. J Lipid Res 2005; 46(12):2706–16.PubMedCrossRefGoogle Scholar
  61. 61.
    Lamour NF, Stahelin RV, Wijesinghe DS et al. Ceramide kinase uses ceramide provided by ceramide transport protein: localization to organelles of eicosanoid synthesis. J Lipid Res 2007; 48(6):1293–304.PubMedCrossRefGoogle Scholar
  62. 62.
    Kumagai K, Yasuda S, Okemoto K et al. CERT mediates intermembrane transfer of various molecular species of ceramides. J Biol Chem 2005; 280(8):6488–95.PubMedCrossRefGoogle Scholar
  63. 63.
    Boath A, Graf C, Lidome E et al. Regulation and traffic of ceramide 1-phosphate produced by ceramide kinase: comparative analysis to glucosylceramide and sphingomyelin. J Biol Chem 2008; 283(13):8517–26.PubMedCrossRefGoogle Scholar
  64. 64.
    Sugiura M, Kono K, Liu H et al. Ceramide kinase, a novel lipid kinase. Molecular cloning and functional characterization. J Biol Chem 2002; 277(26):23294–300.PubMedCrossRefGoogle Scholar
  65. 65.
    Mitsutake S, Yokose U, Kato M et al. The generation and behavioral analysis of ceramide kinase-null mice, indicating a function in cerebellar Purkinje cells. Biochem Biophys Res Commun 2007; 363(3):519–24.PubMedCrossRefGoogle Scholar
  66. 66.
    Graf C, Zemann B, Rovina P et al. Neutropenia with impaired immune response to Streptococcus pneumoniae in ceramide kinase-deficient mice. J Immunol 2008; 180(5):3457–66.PubMedGoogle Scholar
  67. 67.
    Bornancin F, Mechtcheriakova D, Stora S et al. Characterization of a ceramide kinase-like protein. Biochim Biophys Acta 2005; 1687(1–3):31–43.PubMedGoogle Scholar
  68. 68.
    Inagaki Y, Mitsutake S, Igarashi Y. Identification of a nuclear localization signal in the retinitis pigmentosa-mutated RP26 protein, ceramide kinase-like protein. Biochem Biophys Res Commun 2006; 343(3):982–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Boudker O, Futerman AH. Detection and characterization of ceramide-1-phosphate phosphatase activity in rat liver plasma membrane. J Biol Chem 1993; 268(29):22150–5.PubMedGoogle Scholar
  70. 70.
    Shinghal R, Scheller RH, Bajjalieh SM. Ceramide 1-phosphate phosphatase activity in brain. J Neurochem 1993; 61(6):2279–85.PubMedCrossRefGoogle Scholar
  71. 71.
    Brindley DN, Xu J, Jasinska R et al. Analysis of ceramide 1-phosphate and sphingosine-1-phosphate phosphatase activities. Methods Enzymol 2000; 311:233–44.PubMedCrossRefGoogle Scholar
  72. 72.
    Futerman AH, van Meer G. The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol 2004; 5(7):554–65.PubMedCrossRefGoogle Scholar
  73. 73.
    Sabourdy F, Kedjouar B, Sorli SC et al. Functions of sphingolipid metabolism in mammals—lessons from genetic defects. Biochim Biophys Acta 2008; 1781(4):145–83.PubMedGoogle Scholar
  74. 74.
    Duan RD, Cheng Y, Hansen G et al. Purification, localization and expression of human intestinal alkaline sphingomyelinase. J Lipid Res 2003; 44(6):1241–50.PubMedCrossRefGoogle Scholar
  75. 75.
    Schissel SL, Keesler GA, Schuchman EH et al. 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.PubMedCrossRefGoogle Scholar
  76. 76.
    Schissel SL, Schuchman EH, Williams KJ et al. Zn2+-stimulated sphingomyelinase is secreted by many cell types and is a product of the acid sphingomyelinase gene. J Biol Chem 1996; 271(31):18431–6.PubMedCrossRefGoogle Scholar
  77. 77.
    Brady RO, Kanfer JN, Mock MB et al. The metabolism of sphingomyelin. II. Evidence of an enzymatic deficiency in Niemann-Pick diseae. Proc Natl Acad Sci USA 1966; 55(2):366–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Horinouchi K, Erlich S, Perl DP et al. Acid sphingomyelinase deficient mice: a model of types A and B Niemann-Pick disease. Nat Genet 1995; 10(3):288–93.PubMedCrossRefGoogle Scholar
  79. 79.
    Marathe S, Miranda SR, Devlin C et al. Creation of a mouse model for nonneurological (type B) Niemann-Pick disease by stable, low level expression of lysosomal sphingomyelinase in the absence of secretory sphingomyelinase: relationship between brain intra-lysosomal enzyme activity and central nervous system function. Hum Mol Genet 2000; 9(13):1967–76.PubMedCrossRefGoogle Scholar
  80. 80.
    Sawai H, Domae N, Nagan N et al. Function of the cloned putative neutral sphingomyelinase as lyso-platelet activating factor-phospholipase C. J Biol Chem 1999; 274(53):38131–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Zumbansen M, Stoffel W. Neutral sphingomyelinase 1 deficiency in the mouse causes no lipid storage disease. Mol Cell Biol 2002; 22(11):3633–8.PubMedCrossRefGoogle Scholar
  82. 82.
    Tani M, Hannun YA. Neutral sphingomyelinase 2 is palmitoylated on multiple cysteine residues. Role of palmitoylation in subcellular localization. J Biol Chem 2007; 282(13):10047–56.PubMedCrossRefGoogle Scholar
  83. 83.
    Marchesini N, Osta W, Bielawski J et al. Role for mammalian neutral sphingomyelinase 2 in confluence-induced growth arrest of MCF7 cells. J Biol Chem 2004; 279(24):25101–11.PubMedCrossRefGoogle Scholar
  84. 84.
    Stoffel W, Jenke B, Blöck B et al. Neutral sphingomyelinase 2 (smpd3) in the control of postnatal growth and development. Proc Natl Acad Sci USA 2005; 102(12):4554–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Stoffel W, Jenke B, Holz B et al. Neutral sphingomyelinase (SMPD3) deficiency causes a novel form of chondrodysplasia and dwarfism that is rescued by Col2A1-driven smpd3 transgene expression. Am J Pathol 2007; 171(1):153–61.PubMedCrossRefGoogle Scholar
  86. 86.
    Krut O, Wiegmann K, Kashkar H et al. Novel tumor necrosis factor-responsive mammalian neutral sphingomyelinase-3 is a C-tail-anchored protein. J Biol Chem 2006; 281(19):13784–93.PubMedCrossRefGoogle Scholar
  87. 87.
    Corcoran CA, He Q, Ponnusamy S et al. Neutral sphingomyelinase-3 is a DNA damage and nongenotoxic stress-regulated gene that is deregulated in human malignancies. Mol Cancer Res 2008; 6(5):795–807.PubMedCrossRefGoogle Scholar
  88. 88.
    Momoi T, Ben-Yoseph Y, Nadler HL. Substrate-specificities of acid and alkaline ceramidases in fibroblasts from patients with Farber disease and controls. Biochem J 1982; 205(2):419–25.PubMedGoogle Scholar
  89. 89.
    Li CM, Park JH, Simonaro CM et al. Insertional mutagenesis of the mouse acid ceramidase gene leads to early embryonic lethality in homozygotes and progressive lipid storage disease in heterozygotes. Genomics 2002; 79(2):218–24.PubMedCrossRefGoogle Scholar
  90. 90.
    Tani M, Iida H, Ito M. O-glycosylation of mucin-like domain retains the neutral ceramidase on the plasma membranes as a type II integral membrane protein. J Biol Chem 2003; 278(12):10523–30.PubMedCrossRefGoogle Scholar
  91. 91.
    Tani M, Igarashi Y, Ito M. Involvement of neutral ceramidase in ceramide metabolism at the plasma membrane and in extracellular milieu. J Biol Chem 2005; 280(44):36592–600.PubMedCrossRefGoogle Scholar
  92. 92.
    Kono M, Dreier JL, Ellis JM et al. Neutral ceramidase encoded by the Asah2 gene is essential for the intestinal degradation of sphingolipids. J Biol Chem 2006; 281(11):7324–31.PubMedCrossRefGoogle Scholar
  93. 93.
    Ohlsson L, Palmberg C, Duan RD et al. Purification and characterization of human intestinal neutral ceramidase. Biochimie 2007; 89(8):950–60.PubMedCrossRefGoogle Scholar
  94. 94.
    Sun W, Xu R, Hu W et al. Upregulation of the human alkaline ceramidase 1 and acid ceramidase mediates calcium-induced differentiation of epidermal keratinocytes. J Invest Dermatol 2008; 128(2):389–97.PubMedCrossRefGoogle Scholar
  95. 95.
    Xu R, Jin J, Hu W et al. Golgi alkaline ceramidase regulates cell proliferation and survival by controlling levels of sphingosine and S1P. Faseb J 2006; 20(11):1813–25.PubMedCrossRefGoogle Scholar
  96. 96.
    Mao C, Xu R, Szulc ZM et al. Cloning and characterization of a novel human alkaline ceramidase. A mammalian enzyme that hydrolyzes phytoceramide. J Biol Chem 2001; 276(28):26577–88.PubMedCrossRefGoogle Scholar
  97. 97.
    Mao C, Obeid LM. Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine and sphingosine-1-phosphate. Biochim Biophys Acta 2008; 1781(9):424–34.PubMedGoogle Scholar
  98. 98.
    Mao C, Xu R, Szulc ZM et al. Cloning and characterization of a mouse endoplasmic reticulum alkaline ceramidase: an enzyme that preferentially regulates metabolism of very long chain ceramides. J Biol Chem 2003; 278(33):31184–91.PubMedCrossRefGoogle Scholar
  99. 99.
    Wattenberg BW, Pitson SM, Raben DM. The sphingosine and diacylglycerol kinase superfamily of signaling kinases: localization as a key to signaling function. J Lipid Res 2006; 47(6):1128–39.PubMedCrossRefGoogle Scholar
  100. 100.
    Johnson KR, Becker KP, Facchinetti MM et al. PKC-dependent activation of sphingosine kinase 1 and translocation to the plasma membrane. Extracellular release of sphingosine-1-phosphate induced by phorbol 12-myristate 13-acetate (PMA). J Biol Chem 2002; 277(38):35257–62.PubMedCrossRefGoogle Scholar
  101. 101.
    Pitson SM, Moretti PA, Zebol JR et al. Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. Embo J 2003; 22(20):5491–500.PubMedCrossRefGoogle Scholar
  102. 102.
    Buehrer BM, Bardes ES, Bell RM. Protein kinase C-dependent regulation of human erythroleukemia (HEL) cell sphingosine kinase activity. Biochim Biophys Acta 1996; 1303(3):233–42.PubMedGoogle Scholar
  103. 103.
    Yamanaka M, Shegogue D, Pei H et al. Sphingosine kinase 1 (SPHK1) is induced by transforming growth factor-beta and mediates TIMP-1 up-regulation. J Biol Chem 2004; 279(52):53994–4001.PubMedCrossRefGoogle Scholar
  104. 104.
    Nakade Y, Banno Y, T-Koizumi K et al. Regulation of sphingosine kinase 1 gene expression by protein kinase C in a human leukemia cell line, MEG-O1. Biochim Biophys Acta 2003; 1635(2–3):104–16.PubMedGoogle Scholar
  105. 105.
    Olivera A, Kohama T, Edsall L et al. Sphingosine kinase expression increases intracellular sphingosine-1-phosphate and promotes cell growth and survival. J Cell Biol 1999; 147(3):545–58.PubMedCrossRefGoogle Scholar
  106. 106.
    Ancellin N, Colmont C, Su J et al. Extracellular export of sphingosine kinase-1 enzyme. Sphingosine-1-phosphate generation and the induction of angiogenic vascular maturation. J Biol Chem 2002; 277(8):6667–75.PubMedCrossRefGoogle Scholar
  107. 107.
    Inagaki Y, Li PY, Wada A et al. Identification of functional nuclear export sequences in human sphingosine kinase 1. Biochem Biophys Res Commun 2003; 311(1):168–73.PubMedCrossRefGoogle Scholar
  108. 108.
    Thompson CR, Iyer SS, Melrose N et al. Sphingosine kinase 1 (SK1) is recruited to nascent phagosomes in human macrophages: inhibition of SK1 translocation by Mycobacterium tuberculosis. J Immunol 2005; 174(6):3551–61.PubMedGoogle Scholar
  109. 109.
    Stahelin RV, Hwang JH, Kim JH et al. The mechanism of membrane targeting of human sphingosine kinase 1. J Biol Chem 2005.Google Scholar
  110. 110.
    Pitson SM, Xia P, Leclercq TM et al. Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling. J Exp Med 2005; 201(1):49–54.PubMedCrossRefGoogle Scholar
  111. 111.
    Olivera A, Spiegel S. Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature 1993; 365(6446):557–60.PubMedCrossRefGoogle Scholar
  112. 112.
    Edsall LC, Pirianov GG, Spiegel S. Involvement of sphingosine-1-phosphate in nerve growth factor-mediated neuronal survival and differentiation. J Neurosci 1997; 17(18):6952–60.PubMedGoogle Scholar
  113. 113.
    Shu X, Wu W, Mosteller RD et al. Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Mol Cell Biol 2002; 22(22):7758–68.PubMedCrossRefGoogle Scholar
  114. 114.
    Sarkar S, Maceyka M, Hait NC et al. Sphingosine kinase 1 is required for migration, proliferation and survival of MCF-7 human breast cancer cells. FEBS Lett 2005; 579(24):5313–7.PubMedCrossRefGoogle Scholar
  115. 115.
    El-Shewy HM, Johnson KR, Lee MH et al. Insulin-like growth factors mediate heterotrimeric G protein-dependent ERK1/2 activation by transactivating sphingosine-1-phosphate receptors. J Biol Chem 2006.Google Scholar
  116. 116.
    Ma M M, Chen JL, Wang GG et al. Sphingosine kinase 1 participates in insulin signalling and regulates glucose metabolism and homeostasis in KK/Ay diabetic mice. Diabetologia 2007.Google Scholar
  117. 117.
    Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 2003; 4(5):397–407.PubMedCrossRefGoogle Scholar
  118. 118.
    Taha TA, Hannun YA, Obeid LM. Sphingosine kinase: biochemical and cellular regulation and role in disease. J Biochem Mol Biol 2006; 39(2):113–31.PubMedGoogle Scholar
  119. 119.
    Igarashi N, Okada T, Hayashi S et al. Sphingosine kinase 2 is a nuclear protein and inhibits DNA synthesis. J Biol Chem 2003; 278(47):46832–9.PubMedCrossRefGoogle Scholar
  120. 120.
    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(2):229–37.PubMedCrossRefGoogle Scholar
  121. 121.
    Venkataraman K, Thangada S, Michaud J et al. Extracellular export of sphingosine kinase-1a contributes to the vascular S1P gradient. Biochem J 2006; 397(3):461–71.PubMedCrossRefGoogle Scholar
  122. 122.
    Cuvillier O. Sphingosine kinase-1—a potential therapeutic target in cancer. Anticancer Drugs 2007; 18(2):105–10.PubMedCrossRefGoogle Scholar
  123. 123.
    Bonhoure E, Lauret A, Barnes DJ et al. Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukemia cells. Leukemia 2008.Google Scholar
  124. 124.
    Taha TA, Osta W, Kozhaya L et al. Down-regulation of sphingosine kinase-1 by DNA damage: dependence on proteases and p53. J Biol Chem 2004; 279(19):20546–54.PubMedCrossRefGoogle Scholar
  125. 125.
    Taha TA, Kitatani K, Bielawski J et al. Tumor necrosis factor induces the loss of sphingosine kinase-1 by a cathepsin B-dependent mechanism. J Biol Chem 2005; 280(17):17196–202.PubMedCrossRefGoogle Scholar
  126. 126.
    Taha TA, El-Alwani M, Hannun YA et al. Sphingosine kinase-1 is cleaved by cathepsin B in vitro: identification of the initial cleavage sites for the protease. FEBS Lett 2006; 580(26):6047–54.PubMedCrossRefGoogle Scholar
  127. 127.
    Maceyka M, Sankala H, Hait NC et al. Sphk1 and Sphk2: Sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. J Biol Chem 2005.Google Scholar
  128. 128.
    Mitra P, Oskeritzian CA, Payne SG et al. Role of ABCC1 in export of sphingosine-1-phosphate from mast cells. Proc Natl Acad Sci USA 2006; 103(44):16394–9.PubMedCrossRefGoogle Scholar
  129. 129.
    Le Stunff H, Giussani P, Maceyka M et al. Recycling of sphingosine is regulated by the concerted actions of sphingosine-1-phosphate phosphohydrolase 1 and sphingosine kinase 2. J Biol Chem 2007; 282(47):34372–80.PubMedCrossRefGoogle Scholar
  130. 130.
    Allende ML, Sasaki T, Kawai H et al. Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. J Biol Chem 2004; 279(50):52487–92.PubMedCrossRefGoogle Scholar
  131. 131.
    Kohno M, Momoi M, Oo ML et al. Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol Cell Biol 2006; 26(19):7211–23.PubMedCrossRefGoogle Scholar
  132. 132.
    Kawamori T, Kaneshiro T, Okumura M et al. Role for sphingosine kinase 1 in colon carcinogenesis. Faseb J 2008.Google Scholar
  133. 133.
    Snider AJ, Kawamori T, Bradshaw SG et al. A role for sphingosine kinase 1 in dextran sulfate sodium-induced colitis. Faseb J 2008.Google Scholar
  134. 134.
    Mizugishi K, Yamashita T, Olivera A et al. Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol 2005; 25(24):11113–21.PubMedCrossRefGoogle Scholar
  135. 135.
    Liu Y, Wada R, Yamashita T et al. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest 2000; 106(8):951–61.PubMedCrossRefGoogle Scholar
  136. 136.
    Mizugishi K, Li C, Olivera A et al. Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice. J Clin Invest 2007; 117(10):2993–3006.PubMedCrossRefGoogle Scholar
  137. 137.
    Pyne S, Pyne NJ. Sphingosine-1-phosphate signalling and termination at lipid phosphate receptors. Biochim Biophys Acta 2002; 1582(1–3):121–31.PubMedGoogle Scholar
  138. 138.
    Pyne S, Long JS, Ktistakis NT et al. Lipid phosphate phosphatases and lipid phosphate signalling. Biochem Soc Trans 2005; 33(Pt 6):1370–4.PubMedGoogle Scholar
  139. 139.
    Alderton F, Darroch P, Sambi B et al. G-protein-coupled receptor stimulation of the p42/p44 mitogen-activated protein kinase pathway is attenuated by lipid phosphate phosphatases 1, 1a and 2 in human embryonic kidney 293 cells. J Biol Chem 2001; 276(16):13452–60.PubMedCrossRefGoogle Scholar
  140. 140.
    Long J, Darroch P, Wan KF et al. Regulation of cell survival by lipid phosphate phosphatases involves the modulation of intracellular phosphatidic acid and sphingosine-1-phosphate pools. Biochem J 2005; 391(Pt 1):25–32.PubMedGoogle Scholar
  141. 141.
    Delon C, Manifava M, Wood E et al. Sphingosine kinase 1 is an intracellular effector of phosphatidic acid. J Biol Chem 2004; 279(43):44763–74.PubMedCrossRefGoogle Scholar
  142. 142.
    Boujaoude LC, Bradshaw-Wilder C, Mao C et al. Cystic fibrosis transmembrane regulator regulates uptake of sphingoid base phosphates and lysophosphatidic acid: modulation of cellular activity of sphingosine-1-phosphate. J Biol Chem 2001; 276(38):35258–64.PubMedCrossRefGoogle Scholar
  143. 143.
    Pyne S, Kong KC, Darroch PI. Lysophosphatidic acid and sphingosine-1-phosphate biology: the role of lipid phosphate phosphatases. Semin Cell Dev Biol 2004; 15(5):491–501.PubMedCrossRefGoogle Scholar
  144. 144.
    Mandala SM, Thornton R, Tu Z et al. Sphingoid base 1-phosphate phosphatase: a key regulator of sphingolipid metabolism and stress response. Proc Natl Acad Sci USA 1998; 95(1):150–5.PubMedCrossRefGoogle Scholar
  145. 145.
    Mandala SM, Thornton R, Galve-Roperh I et al. Molecular cloning and characterization of a lipid phosphohydrolase that degrades sphingosine-1-phosphate and induces cell death. Proc Natl Acad Sci USA 2000; 97(14):7859–64.PubMedCrossRefGoogle Scholar
  146. 146.
    Ogawa C, Kihara A, Gokoh M et al. Identification and characterization of a novel human sphingosine-1-phosphate phosphohydrolase, hSPP2. J Biol Chem 2003; 278(2):1268–72.PubMedCrossRefGoogle Scholar
  147. 147.
    Le Stunff H, Galve-Roperh I, Peterson C et al. Sphingosine-1-phosphate phosphohydrolase in regulation of sphingolipid metabolism and apoptosis. J Cell Biol 2002; 158(6):1039–49.PubMedCrossRefGoogle Scholar
  148. 148.
    Kihara A, Sano T, Iwaki S et al. Transmembrane topology of sphingoid long-chain base-1-phosphate phosphatase, Lcb3p. Genes Cells 2003; 8(6):525–35.PubMedCrossRefGoogle Scholar
  149. 149.
    Johnson KR, Johnson KY, Becker KP et al. Role of human sphingosine-1-phosphate phosphatase 1 in the regulation of intra-and extracellular sphingosine-1-phosphate levels and cell viability. J Biol Chem 2003; 278(36):34541–7.PubMedCrossRefGoogle Scholar
  150. 150.
    Le Stunff H, Peterson C, Liu H et al. Sphingosine-1-phosphate and lipid phosphohydrolases. Biochim Biophys Acta 2002; 1582(1–3):8–17.PubMedGoogle Scholar
  151. 151.
    Mechtcheriakova D, Wlachos A, Sobanov J et al. Sphingosine-1-phosphate phosphatase 2 is induced during inflammatory responses. Cell Signal 2006.Google Scholar
  152. 152.
    Ikeda M, Kihara A, Igarashi Y. Sphingosine-1-phosphate lyase SPL is an endoplasmic reticulum-resident, integral membrane protein with the pyridoxal 5′-phosphate binding domain exposed to the cytosol. Biochem Biophys Res Commun 2004; 325(1):338–43.PubMedCrossRefGoogle Scholar
  153. 153.
    Stoffel W, LeKim D, Sticht G. Distribution and properties of dihydrosphingosine-1-phosphate aldolase (sphinganine-1-phosphate alkanal-lyase). Hoppe Seylers Z Physiol Chem 1969; 350(10):1233–41.PubMedGoogle Scholar
  154. 154.
    Schwab SR, Pereira JP, Matloubian M et al. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 2005; 309(5741):1735–9.PubMedCrossRefGoogle Scholar
  155. 155.
    Fyrst H, Saba JD. Sphingosine-1-phosphate lyase in development and disease: sphingolipid metabolism takes flight. Biochim Biophys Acta 2008; 1781(9):448–58.PubMedGoogle Scholar
  156. 156.
    Mendel J, Heinecke K, Fyrst H et al. Sphingosine phosphate lyase expression is essential for normal development in Caenorhabditis elegans. J Biol Chem 2003; 278(25):22341–9.PubMedCrossRefGoogle Scholar
  157. 157.
    Li G, Foote C, Alexander S et al. Sphingosine-1-phosphate lyase has a central role in the development of Dictyostelium discoideum. Development 2001; 128(18):3473–83.PubMedGoogle Scholar
  158. 158.
    Schmahl J, Raymond CS, Soriano P. PDGF signaling specificity is mediated through multiple immediate early genes. Nat Genet 2007; 39(1):52–60.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  • Christopher R. Gault
    • 1
  • Lina M. Obeid
    • 1
    • 2
  • Yusuf A. Hannun
    • 1
  1. 1.Departments of Biochemistry and Molecular BiologyMedical University of South CarolinaCharlestonUSA
  2. 2.Department of MedicineMedical University of South CarolinaCharlestonUSA

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