Table of Contents Author Guidelines Submit a Manuscript
Journal of Lipids
Volume 2011, Article ID 724015, 9 pages
http://dx.doi.org/10.1155/2011/724015
Research Article

Dihydroceramide Desaturase Inhibition by a Cyclopropanated Dihydroceramide Analog in Cultured Keratinocytes

1CECAD Cologne Platform Lipidomics, Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Goldenfelsstraße 19-21, 50935 Cologne, Germany
2LIMES Program Unit Membrane Biology and Lipid Biochemistry, Kekulé Institute of Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany

Received 1 July 2010; Revised 21 September 2010; Accepted 27 October 2010

Academic Editor: Michel Lagarde

Copyright © 2011 Susanne Brodesser and Thomas Kolter. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. N. Bartke and Y. A. Hannun, “Bioactive sphingolipids: metabolism and function,” Journal of Lipid Research, vol. 50, pp. S91–96, 2009. View at Publisher · View at Google Scholar · View at Scopus
  2. T. Wennekes, R. J. B. H. N. van den Berg, R. G. Boot, G. A. van der Marel, H. S. Overkleeft, and J. M. F. G. Aerts, “Glycosphingolipids—nature, function, and pharmacological modulation,” Angewandte Chemie - International Edition, vol. 48, no. 47, pp. 8848–8869, 2009. View at Publisher · View at Google Scholar · View at Scopus
  3. A. Delgado, J. Casas, A. Llebaria, J. L. Abad, and G. Fabriás, “Chemical tools to investigate sphingolipid metabolism and functions,” ChemMedChem, vol. 2, no. 5, pp. 580–606, 2007. View at Publisher · View at Google Scholar · View at Scopus
  4. C. Michel, G. van Echten-Deckert, J. Rother, K. Sandhoff, E. Wang, and A. H. Merrill Jr., “Characterization of ceramide synthesis. A dihydroceramide desaturase introduces the 4,5-trans-double bond of sphingosine at the level of dihydroceramide,” The Journal of Biological Chemistry, vol. 272, no. 36, pp. 22432–22437, 1997. View at Publisher · View at Google Scholar · View at Scopus
  5. L. Geeraert, G. P. Mannaerts, and P. P. van Veldhoven, “Conversion of dihydroceramide into ceramide: involvement of a desaturase,” Biochemical Journal, vol. 327, no. 1, pp. 125–132, 1997. View at Google Scholar · View at Scopus
  6. C. Michel and G. van Echten-Deckert, “Conversion of dihydroceramide to ceramide occurs at the cytosolic face of the endoplasmic reticulum,” FEBS Letters, vol. 416, no. 2, pp. 153–155, 1997. View at Publisher · View at Google Scholar · View at Scopus
  7. T. Mikami, M. Kashiwagi, K. Tsuchihashi, T. Akino, and S. Gasa, “Substrate specificity and some other enzymatic properties of dihydroceramide desaturase (Ceramide synthase) in fetal rat skin,” Journal of Biochemistry, vol. 123, no. 5, pp. 906–911, 1998. View at Google Scholar · View at Scopus
  8. E. Beauchamp, D. Goenaga, J. Le Bloc'h, D. Catheline, P. Legrand, and V. Rioux, “Myristic acid increases the activity of dihydroceramide Δ4-desaturase 1 through its N-terminal myristoylation,” Biochimie, vol. 89, no. 12, pp. 1553–1561, 2007. View at Publisher · View at Google Scholar · View at Scopus
  9. Y. Mizutani, A. Kihara, and Y. Igarashi, “Identification of the human sphingolipid C4-hydroxylase, hDES2, and its up-regulation during keratinocyte differentiation,” FEBS Letters, vol. 563, no. 1–3, pp. 93–97, 2004. View at Publisher · View at Google Scholar · View at Scopus
  10. C. K. Savile, G. Fabriàs, and P. H. Buist, “Dihydroceramide Δ4 desaturase initiates substrate oxidation at C-4,” Journal of the American Chemical Society, vol. 123, no. 19, pp. 4382–4385, 2001. View at Publisher · View at Google Scholar · View at Scopus
  11. A. Bielawska, H. M. Crane, D. Liotta, L. M. Obeid, and Y. A. Hannun, “Selectivity of ceramide-mediated biology. Lack of activity of erythro- dihydroceramide,” The Journal of Biological Chemistry, vol. 268, no. 35, pp. 26226–26232, 1993. View at Google Scholar · View at Scopus
  12. H. Fyrst and J. D. Saba, “An update on sphingosine-1-phosphate and other sphingolipid mediators,” Nature Chemical Biology, vol. 6, no. 7, pp. 489–497, 2010. View at Publisher · View at Google Scholar
  13. W. L. Holland, J. T. Brozinick, L.-P. Wang et al., “Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance,” Cell Metabolism, vol. 5, no. 3, pp. 167–179, 2007. View at Publisher · View at Google Scholar · View at Scopus
  14. G. Triola, G. Fabriàs, and A. Llebaria, “Synthesis of a cyclopropene analogue of ceramide, a potent inhibitor of dihydroceramide desaturase,” Angewandte Chemie - International Edition, vol. 40, no. 10, pp. 1960–1962, 2001. View at Publisher · View at Google Scholar · View at Scopus
  15. G. Triola, G. Fabriàs, J. Casas, and A. Llebaria, “Synthesis of cyclopropene analogues of ceramide and their effect on dihydroceramide desaturase,” Journal of Organic Chemistry, vol. 68, no. 26, pp. 9924–9932, 2003. View at Publisher · View at Google Scholar · View at Scopus
  16. C. Bedia, G. Triola, J. Casas, A. Llebaria, and G. Fabriàs, “Analogs of the dihydroceramide desaturase inhibitor GT11 modified at the amide function: synthesis and biological activities,” Organic and Biomolecular Chemistry, vol. 3, no. 20, pp. 3707–3712, 2005. View at Publisher · View at Google Scholar · View at Scopus
  17. J. M. Munoz-Olaya, X. Matabosch, C. Bedia et al., “Synthesis and biological activity of a novel inhibitor of dihydroceramide desaturase,” ChemMedChem, vol. 3, no. 6, pp. 946–953, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. G. Triola, G. Fabrias, M. Dragusin et al., “Specificity of the dihydroceramide desaturase inhibitor N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl] octanamide (GT11) in primary cultured cerebellar neurons,” Molecular Pharmacology, vol. 66, no. 6, pp. 1671–1678, 2004. View at Publisher · View at Google Scholar · View at Scopus
  19. P. Signorelli, J. M. Munoz-Olaya, V. Gagliostro, J. Casas, R. Ghidoni, and G. Fabriàs, “Dihydroceramide intracellular increase in response to resveratrol treatment mediates autophagy in gastric cancer cells,” Cancer Letters, vol. 282, no. 2, pp. 238–243, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. B. Ogretmen, B. J. Pettus, M. J. Rossi et al., “Biochemical mechanisms of the generation of endogenous long chain ceramide in response to exogenous short chain ceramide in the A549 human lung adenocarcinoma cell line. Role for endogenous ceramide in mediating the action of exogenous ceramide,” The Journal of Biological Chemistry, vol. 277, no. 15, pp. 12960–12969, 2002. View at Publisher · View at Google Scholar · View at Scopus
  21. R. B. Silverman, C. Z. Ding, J. L. Borrillo, and J. T. Chang, “Mechanism-based enzyme inactivation via a diactivated cyclopropane intermediate,” Journal of the American Chemical Society, vol. 115, pp. 2982–2983, 1993. View at Google Scholar
  22. P. Garner, J. M. Park, and E. Malecki, “A stereodivergent synthesis of D-erythro-sphingosine and D-threo-sphingosine from L-serine,” Journal of Organic Chemistry, vol. 53, no. 18, pp. 4395–4398, 1988. View at Google Scholar · View at Scopus
  23. P. Herold, “Synthesis of D-erythro- and D-threo-sphingosine derivatives from L-serine,” Helvetica Chimica Acta, vol. 71, no. 2, pp. 354–362, 1988. View at Google Scholar · View at Scopus
  24. J. Furukawa, N. Kawabata, and J. Nishimura, “Synthesis of cyclopropanes by the reaction of olefins with dialkylzinc and methylene iodide,” Tetrahedron, vol. 24, no. 1, pp. 53–58, 1968. View at Google Scholar · View at Scopus
  25. G. van Echten-Deckert, A. Giannis, A. Schwarz, A. H. Futerman, and K. Sandhoff, “1-Methylthiodihydroceramide, a novel analog of dihydroceramide, stimulates sphinganine degradation resulting in decreased de novo sphingolipid biosynthesis,” The Journal of Biological Chemistry, vol. 273, no. 2, pp. 1184–1191, 1998. View at Publisher · View at Google Scholar · View at Scopus
  26. W. M. Holleran, Y. Takagi, and Y. Uchida, “Epidermal sphingolipids: metabolism, function, and roles in skin disorders,” FEBS Letters, vol. 580, no. 23, pp. 5456–5466, 2006. View at Publisher · View at Google Scholar · View at Scopus
  27. Y. Uchida and W. M. Holleran, “Omega-O-acylceramide, a lipid essential for mammalian survival,” Journal of Dermatological Science, vol. 51, no. 2, pp. 77–87, 2008. View at Publisher · View at Google Scholar · View at Scopus
  28. Y. Mizutani, S. Mitsutake, K. Tsuji, A. Kihara, and Y. Igarashi, “Ceramide biosynthesis in keratinocyte and its role in skin function,” Biochimie, vol. 91, no. 6, pp. 784–790, 2009. View at Publisher · View at Google Scholar · View at Scopus
  29. B. Breiden, H. Gallala, T. Doering, and K. Sandhoff, “Optimization of submerged keratinocyte cultures for the synthesis of barrier ceramides,” European Journal of Cell Biology, vol. 86, no. 11-12, pp. 657–673, 2007. View at Publisher · View at Google Scholar · View at Scopus
  30. K. A. Karlsson and I. Pascher, “Thin-layer chromatography of ceramides,” Journal of Lipid Research, vol. 12, no. 4, pp. 466–472, 1971. View at Google Scholar · View at Scopus
  31. S. Takagi, H. Tojo, S. Tomita et al., “Alteration of the 4-sphingenine scaffolds of ceramides in keratinocyte-specific Arnt-deficient mice affects skin barrier function,” The Journal of Clinical Investigation, vol. 112, no. 9, pp. 1372–1382, 2003. View at Publisher · View at Google Scholar · View at Scopus
  32. P. Ternes, S. Franke, U. Zähringer, P. Sperling, and E. Heinz, “Identification and characterization of a sphingolipid Δ4-desaturase family,” The Journal of Biological Chemistry, vol. 277, no. 28, pp. 25512–25518, 2002. View at Publisher · View at Google Scholar · View at Scopus
  33. F. Omae, M. Miyazaki, A. Enomoto, and A. Suzuki, “Identification of an essential sequence for dihydroceramide C-4 hydroxylase activity of mouse DES2,” FEBS Letters, vol. 576, no. 1-2, pp. 63–67, 2004. View at Publisher · View at Google Scholar · View at Scopus
  34. C. Beckmann, J. Rattke, P. Sperling, E. Heinz, and W. Boland, “Stereochemistry of a bifunctional dihydroceramide δ4- desaturase/hydroxylase from Candida albicans; a key enzyme of sphingolipid metabolism,” Organic and Biomolecular Chemistry, vol. 1, no. 14, pp. 2448–2454, 2003. View at Publisher · View at Google Scholar · View at Scopus
  35. Y. Mizutani, A. Kihara, and Y. Igarashi, “Identification of the human sphingolipid C4-hydroxylase, hDES2, and its up-regulation during keratinocyte differentiation,” FEBS Letters, vol. 563, no. 1–3, pp. 93–97, 2004. View at Publisher · View at Google Scholar · View at Scopus
  36. H. Gallala, O. Macheleidt, T. Doering, V. Schreiner, and K. Sandhoff, “Nitric oxide regulates synthesis of gene products involved in keratinocyte differentiation and ceramide metabolism,” European Journal of Cell Biology, vol. 83, no. 11-12, pp. 667–679, 2004. View at Publisher · View at Google Scholar · View at Scopus
  37. D. R. Roop, H. Huitfeldt, A. Kilkenny, and S. H. Yuspa, “Regulated expression of differentiation-associated keratins in cultured epidermal cells detected by monospecific antibodies to unique peptides of mouse epidermal keratins,” Differentiation, vol. 35, no. 2, pp. 143–150, 1987. View at Google Scholar · View at Scopus
  38. P. K. Raju and R. Reiser, “Inhibition of fatty acyl desaturase by cyclopropene fatty acids,” The Journal of Biological Chemistry, vol. 242, no. 3, pp. 379–384, 1967. View at Google Scholar · View at Scopus
  39. C. R. Vieira, J. M. Munoz-Olaya, J. Sot et al., “Dihydrosphingomyelin impairs HIV-1 infection by rigidifying liquid-ordered membrane domains,” Chemistry and Biology, vol. 17, no. 7, pp. 766–775, 2010. View at Publisher · View at Google Scholar
  40. P. Gangoiti, L. Camacho, L. Arana et al., “Control of metabolism and signaling of simple bioactive sphingolipids: implications in disease,” Progress in Lipid Research, vol. 49, no. 4, pp. 316–334, 2010. View at Publisher · View at Google Scholar