Laboratory of Molecular Neuroscience   printer friendly

The role of sphingolipids and
their key synthesizing and degrading enzymes:

Cerebroside synthase (UDP-galactosyl-ceramide transferase, CGT),
acid (SMPD-1) and neutral sphingomyelinases (SMPD-2 and SMPD-3)


Biochemistry and cell biology of long chain sphingosine bases and sphingolipids galactocerebrosides and sphingomyelin

Genetics, cell biology and biochemistry of sphingolipid synthesizing and degrading enzymes : Cerebroside synthase( UDP-galactosyl-ceramide transferase, CGT), acid (SMPD-1) and neutral sphingomyelinases SMPD-2 and SMPD-3).

Sphingosine bases, dihydrosphingosine and sphingosine, (long chain bases) form the backbone molecule of complex sphingolipids , important building blocks of biological membranes, particularly of myelin of central and peripheral nervous system.

We unravelled the complete biosynthetic and catabolic pathways of long chain sphingosine bases, including the key enzyme in the biosynthesis long chain sphingosine bases, palmitoyl-CoA serine transferase (SPT), which condenses palmitoyl-CoA and serine to 3-keto-2S-sphinganine, the 3-ketosphinganine reductase, a NADPH dependent enzyme, which stereospecifically introduces the 3 R hydroxygroup to sphinganine. After acylation to ceramide the trans double bond is introduced in the acyl-4trans-sphinganine desaturase reaction.


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Figure 1: Sphingolipid Metabolism

The degradation of the long chain bases is initiated by the ATP dependent sphingosine - kinase (SP-1-K) reaction to sphingosine-1-phosphate, which has recently been described as a potential lipid second messenger molecule. SP1-P is cleaved in a pyridoxal phosphate dependent aldolase reaction by SP-1-phosphate aldolase to palmitaldehyde and ethanolamine phosphate. The reutilization of these degradation products in the phospholipid synthesis has been established in this laboratory.

We have recently generated the inducible, conditional SPT-knock out mouse model, the characterization of which is under way.


References
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  2. W. Stoffel, I. Melzner (1980) Studies in vitro on the biosynthesis of ceramide and sphingomyelin A reevaluation of proposed pathways Hoppe-Seyler's Zeitschr. Physiol. Chemie, 361, 755-771
  3. W. Stoffel, K. Dittmar, R. Wilmes (1975) Sphingolipid metabolism in bacteroide aceae Hoppe-Seyler's Zeitschr. Physiol. Chemie, 356, 715-725
  4. W. Stoffel, K. Bister (1974) Studies on the desaturation of sphinganine Hoppe-Seyler's Zeitschr. Physiol. Chemie, 355, 911-923
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  6. W. Stoffel, W. Därr (1974) 2-alkenal reductase. Isolation, properties and specificities Hoppe-Seyler's Zeitschr. Physiol. Chemie, 355, 54-60
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  8. R. Henning, H. Plattner, W. Stoffel (1973) Nature and localization of acidic groups on lysosomal membranes Biochim. Biophys. Acta 330, 61-75
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  10. W. Stoffel, B. Hellenbroich, G. Heimann (1973) Properties and specificities of sphingosine kinase from blood platelets Hoppe-Seyler's Zeitschr. Physiol. Chemie, 354, 1311-1316
  11. D. LeKim, H. Betzing, W. Stoffel (1973) Studies in vivo and in vitro on the methylation of phosphatidyl-N, N-dimethylethanolamine to phosphatidylcholine in rat liver Hoppe-Seyler's Zeitschr. Physiol. Chemie, 354, 437-444
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  16. W. Stoffel (1973 Relationship between sphingolipid and phospholipid metabolism Biochemical Society Transactions, 336-341 )
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  26. R. Henning, H. D. Kaulen, W. Stoffel (1971) Biochemical analysis of the pinocytotic process III. Subcellular distribution and metabolic effects of 3H triton WR-1339 Hoppe-Seyler's Zeitschr. Physiol. Chemie, 352, 1347-1358
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  29. W. Stoffel, E. Binczek (1971) Metabolism of sphingosine bases XVI. Studies on the stereospecifity of the introduction of the hydroxy group of 4D-hydroxysphinganine (phytosphingosine) Hoppe-Seyler's Zeitschr. Physiol. Chemie, 352, 1065-1072
  30. W. Stoffel, D. LeKim (1971) On the stereospecificity of the biochemical dehydrogenation of the 1-O-alkyl-glyceryl to the 1-O-alk-1'-enyl glyceryl ether bond Hoppe-Seyler's Zeitschr. Physiol. Chemie, 352, 501-511
  31. W. Stoffel, W. Ecker, H. Assad, H. Sprecher (1970) Studies on the mechanism of the retroconversion of C22-polyenic fatty acids to their C20-homologues Hoppe-Seyler's Zeitschr. Physiol. Chemie, 351, 1545-1554
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  34. W. Stoffel, G. Assmann (1970) Metabolism of sphingosine bases XV. Enzymatic degradation of 4t-sphingenine 1-phosphate (sphingosine 1-phosphate) to 2t-hexadecen-1-al and ethanolamine phosphate Hoppe-Seyler's Zeitschr. Physiol. Chemie, 351, 1041-1049
  35. W. Stoffel, D. LeKim, G. Heyn (1970) Metabolism of sphingosine bases XIV. Sphinganine (dihydrosphingosine), an effective donor of the alk-1'-enyl chain of plasmalogens Hoppe-Seyler's Zeitschr. Physiol. Chemie, 351, 875-883
  36. W. Stoffel, G. Assmann, E. Binczek (1970) Metabolism of sphingosine bases XIII. Enzymatic synthesis of 1-phosphate esters of 4t-sphingenine (sphingosine), sphinganine (dihydrosphingosine), 4-hydroxysphinganine (phytosphingosine) and 3-dehydrosphinganine by erythrocytes Hoppe-Seyler's Zeitschr. Physiol. Chemie, 351, 635-642
  37. W. Stoffel, A. Scheid (1969) Metabolism of sphingosine bases XII. Eicosasphinganine (eicosadihydrosphingosine) and 3-dehydroeicosasphinganine (3-dehydroeicosadihydrosphingosine) Hoppe-Seyler's Zeitschr. Physiol. Chemie, 350, 1593-1604
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  39. W. Stoffel, H. D. Pruss (1969) Monolayer studies with synthetic saturated mono- and polyunsaturated mixed 1,2-diglycerides, 1,2-diacylphosphatidylethanolamines and phosphatidylcholines at the air-water-interface Hoppe-Seyler's Zeitschr. Physiol. Chemie, 350, 1385-1393
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  44. Metabolism of sphingosine bases (1968) VIII. Stereospecifity of the NADPH-dependent reduction reaction of 3-oxodihydrosphingosine (2-amino-1-hydroxyoctadecane-3-one) Hoppe-Seyler's Zeitschr. Physiol. Chemie, 349, 1637-1644
  45. W. Stoffel, R. Henning (1968) Metabolism of sphingosine bases VII. Studies on the metabolism of [1-3H]-erythro-D, L-sphingosine ([1-3H]-4t-sphingenine) during the myelination period of the rat Hoppe-Seyler's Zeitschr. Physiol. Chemie, 349, 1400-1404
  46. W. Stoffel, G. Sticht, D. LeKim (1968) Metabolism of sphingosine bases VI. Synthesis and degradation of sphingosine bases in Hansenual ciferrii Hoppe-Seyler's Zeitschr. Physiol. Chemie, 349, 1149-1156
  47. W. Stoffel, H. G. Schiefer (1968) Biosynthesis and composition of phosphatides in outer and inner mitochondrial membranes Hoppe-Seyler's Zeitschr. Physiol. Chemie, 349, 1017-1026
  48. D. Falke, H. G. Schiefer, W. Stoffel (1967) Lipoid-Analysen bei Riesenzellbildung durch Herpesvirus-Hominis Zeitschrift für Naturforschung, 22b, 1360-1362
  49. W. Stoffel, D. LeKim, G. Sticht (1968) Metabolism of sphingosine bases V. Biosynthesis of dihydrosphingosine in vitro Hoppe-Seyler's Zeitschr. Physiol. Chemie, 349, 664-670
  50. W. Stoffel, D. LeKim, G. Sticht (1967) Metabolism of sphingosine bases IV. 2-amino-1-hydroxyoctadecane-3-one (3-oxodihydrosphingosine), the common intermediate in the biosynthesis of dihydrosphingosine and sphingosine and in the degradation of dihydrosphingosine Hoppe-Seyler's Zeitschr. Physiol. Chemie, 348, 1570-1574
  51. W. Stoffel, G. Sticht (1967) Metabolism of sphingosine bases III. Chemical synthesis of 14C and 3H-labeled erythro- and threo-dihydrosphingosines and sphingosines Hoppe-Seyler's Zeitschr. Physiol. Chemie, 348, 1561-1569
  52. W. Stoffel, G. Sticht (1967) Metabolism of sphingosine bases II. Studies on the degradation and transformation of [3-14C]-erythro-D, L-sphingosine, [5-3H]-threo-L-dihydrosphingosine and [3-14C, 1-3H]-erythro-D, L-Dihydrosphingosine in rat liver Hoppe-Seyler's Zeitschr. Physiol. Chemie, 348, 1345-1351
  53. W. Stoffel, G. Sticht (1967) Metabolism of sphingosine bases I. Degradation and incorporation of [3-14C]-erythro-DL-Dihydrosphingosine and [7-3H2]-erythro-DL-sphingosine into sphingolipids of rat liver Hoppe-Seyler's Zeitschr. Physiol. Chemie, 348, 941-943


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