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UDP-Gal: Ceramide Galactosyltransferase (UGT8)

  • Koichi Honke
Reference work entry

Abstract

The biosynthetic pathway of glycosphingolipids (GSLs) begins with monoglycosylation, glucosylation, or galactosylation in mammals, of ceramide. Galactosylation of ceramide is unique in that it takes place at the lumen of the endoplasmic reticulum (ER) while all the other glycosylation reactions of GSLs occur at the Golgi apparatus and that the reaction product, galactosylceramide (GalCer), is only used for the synthesis of the gala series GSLs including sulfatide, while glucosylceramide serves as the precursor for most of GSLs including gangliosides. Synthesis of GalCer is catalyzed by UDP-Gal:ceramide galactosyltransferase (CGT). CGT prefers to 2-hydroxyacylsphingosine, a hydroxy fatty acid (HFA)-containing ceramide, as an acceptor (Morell and Radin 1969) but also acts on normal fatty acid (NFA)-containing ceramides and diglycerides (van der Bijl et al. 1996). CGT was purified homogeneously from rat brain (Schulte and Stoffel 1993) and its cDNA was cloned and characterized independently in three laboratories (Schulte and Stoffel 1993; Stahl et al. 1994; Schaeren-Wiemers et al. 1995). CGT belongs to the family of the ER glucuronyltransferases and exhibits a type I transmembrane topology possessing an ER retention signal in its cytosolic tail. Studies on the knockout mice of CGT have proved that the single enzyme is responsible for the biosynthesis of NFA- and HFA-GalCer in the brain and galactosylalkylacylglycerol (GalEAG) in the testis (Bosio et al. 1996a; Coetzee et al. 1996a; Fujimoto et al. 2000). CGT-deficient mice manifest neurological disorders caused by myelin dysfunction (Bosio et al. 1996a; Coetzee et al. 1996a) and the complete inhibition of spermatogenesis at the late pachytene spermatocyte stage (Fujimoto et al. 2000), indicating that the intermediate products, GalCer and GalEAG, and/or the end products, sulfatide and seminolipid, are indispensable for myelin function and spermatogenesis.

Keywords

Endoplasmic Reticulum Peripheral Nervous System Seminiferous Tubule Endoplasmic Reticulum Lumen Oligodendrocyte Differentiation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Baulieu EE, Robel P, Schumacher M (2001) Neurosteroids: beginning of the story. Int Rev Neurobiol 46:1–32PubMedCrossRefGoogle Scholar
  2. Bosio A, Binczek E, Stoffel W (1996a) Functional breakdown of the lipid bilayer of the myelin membrane in central and peripheral nervous system by disrupted galactocerebroside synthesis. Proc Natl Acad Sci U S A 93:13280–13285PubMedCentralPubMedCrossRefGoogle Scholar
  3. Bosio A, Binczek E, Le Beau MM, Fernald AA, Stofferl W (1996b) The human gene CGT encoding the UDP-galactose ceramide galactosyltransferase (cerebroside synthase): Cloning, characterization, and assignment to human chromosome 4, band q26. Genomics 34:69–75PubMedCrossRefGoogle Scholar
  4. Bosio A, Binczek E, Stoffel W (1996c) Molecular cloning and characterization of the mouse CGT gene encoding UDP-galactose ceramide galactosyltransferase (cerebroside synthetase). Genomics 35:223–226PubMedCrossRefGoogle Scholar
  5. Bosio A, Binczek E, Haupt WF, Stoffel W (1998) Composition and biophysical properties of myelin lipid define the neurological defects in galactocerebroside- and sulfatide-deficient mice. J Neurochem 70:308–315PubMedCrossRefGoogle Scholar
  6. Coetzee T, Fujita N, Dupree J, Shi R, Blight A, Suzuki K, Popko B (1996a) Myelination in the absence of galactocerebroside and sulfatide: normal structure with abnormal function and regional instability. Cell 86:209–219PubMedCrossRefGoogle Scholar
  7. Coetzee T, Li X, Fujita N, Marcus J, Suzuki K, Francke U, Popko B (1996b) Molecular cloning, chromosomal mapping, and characterization of the mouse UDP-galactose:ceramide galactosyltransferase gene. Genomics 35:215–222PubMedCrossRefGoogle Scholar
  8. Coetzee T, Suzuki K, Popko B (1998) New perspectives on the function of myelin galactolipids. Trends Neurosci 21:126–130PubMedCrossRefGoogle Scholar
  9. Dupree JL, Coetzee T, Blight A, Suzuki K, Popko B (1998) Myelin galactolipids are essential for proper node of Ranvier formation in the CNS. J Neurosci 18:1642–1649PubMedGoogle Scholar
  10. Dupree JL, Girault JA, Popko B (1999) Axo-glial interactions regulate the localization of axonal paranodal proteins. J Cell Biol 147:1145–1152PubMedCrossRefGoogle Scholar
  11. Dzięgiel P, Owczarek T, Plazuk E, Gomułkiewicz A, Majchrzak M, Podhorska-Okołów M, Driouch K, Lidereau R, Ugorski M (2010) Ceramide galactosyltransferase (UGT8) is a molecular marker of breast cancer malignancy and lung metastases. Br J Cancer 103:524–531PubMedCentralPubMedCrossRefGoogle Scholar
  12. Fujimoto H, Tadano-Aritomi K, Tokumasu A, Ito K, Hikita T, Suzuki K, Ishizuka I (2000) Requirement of seminolipid in spermatogenesis revealed by UDP-galactose: ceramide galactosyltransferase-deficient mice. J Biol Chem 275:22623–22626PubMedCrossRefGoogle Scholar
  13. Hayashi T, Hayashi E, Fujimoto M, Sprong H, Su T (2012) The lifetime of UDP-galactose:ceramide galactosyltransferase is controlled by a distinct endoplasmic reticulum-associated degradation (ERAD) regulated by sigma-1 receptor chaperones. J Biol Chem 287:43156–43169PubMedCrossRefGoogle Scholar
  14. Hirahara Y, Bansal R, Honke K, Ikenaka K, Wada Y (2004) Sulfatide is a negative regulator of oligodendrocyte differentiation: development in sulfatide-null mice. Glia 45:269–277PubMedCrossRefGoogle Scholar
  15. Honke K, Yamane M, Ishii A, Kobayashi T, Makita A (1996) Purification and characterization of 3′-phosphoadenosine-5′-phosphosulfate:GalCer sulfotransferase from human renal cancer cells. J Biochem 119:421–427PubMedCrossRefGoogle Scholar
  16. Honke K, Hirahara Y, Dupree J, Suzuki K, Popko B, Fukushima K, Fukushima J, Nagasawa T, Yoshida N, Wada Y, Taniguchi N (2002) Paranodal junction formation and spermatogenesis require sulfoglycolipids. Proc Natl Acad Sci U S A 99:4227–4232PubMedCentralPubMedCrossRefGoogle Scholar
  17. Lairson LL, Henrissat B, Davies GJ, Withers SG (2008) Glycosyltransferases: structures, functions, and mechanisms. Annu Rev Biochem 77:521–555PubMedCrossRefGoogle Scholar
  18. Landemaine T, Jackson A, Bellahcene A, Rucci N, Sin S, Abad BM, Sierra A, Boudinet A, Guinebretiere JM, Ricevuto E, Nogues C, Briffod M, Bieche I, Cherel P, Castronovo V, Teti A, Lidereau R, Driouch K (2008) A six-gene signature predicting breast cancer lung metastasis. Cancer Res 68:6092–6099PubMedCrossRefGoogle Scholar
  19. Marcus J, Honigbaum S, Shroff S, Honke K, Rosenbluth J, Dupree JL (2006) Sulfatide is essential for the maintenance of CNS myelin and axon structure. Glia 53:372–381PubMedCrossRefGoogle Scholar
  20. Meixner M, Jungnickel J, Grothe C, Gieselmann V, Eckhardt M (2011) Myelination in the absence of UDP-galactose:ceramide galactosyltransferase and fatty acid 2-hydroxylase. BMC Neurosci 12:22PubMedCentralPubMedCrossRefGoogle Scholar
  21. Morell P, Radin NS (1969) Synthesis of cerebroside by brain from uridine diphosphate galactose- and ceramide-containing hydroxy fatty acid. Biochemistry 8:506–513PubMedCrossRefGoogle Scholar
  22. Moser HM, Karnovsky ML (1959) Studies on the biosynthesis of glycolipids and other lipids of the brain. J Biol Chem 234:1990–1997PubMedGoogle Scholar
  23. Mulichak AM, Losey HC, Lu W, Wawezak Z, Walsh CT, Garavito RM (2003) Structure of the TDP-epi-vancosaminyltransferase GtfA from the chloroeremomycin biosynthetic pathway. Proc Natl Acad Sci U S A 100:9238–9243PubMedCentralPubMedCrossRefGoogle Scholar
  24. Neskovic NM, Mandel P, Gatt S (1981) UDPgalactose:ceramide galactosyltransferase from rat brain. Methods Enzymol 71:521–536PubMedCrossRefGoogle Scholar
  25. Neskovic N, Roussel G, Nussbaum J (1986) UDP-galactose:ceramide galactosyltransferase of rat brain: a new method of purification and production of specific antibodies. J Neurochem 47:1412–1418PubMedCrossRefGoogle Scholar
  26. Saadat L, Dupree JL, Kikus J, Han X, Traka M, Proia RL, Dawson G, Popko B (2010) Absence of oligodendroglial glucosylceramide synthesis does not result in CNS myelin abnormalities of alter the dysmyelinating phenotype of CGT-deficient mice. Glia 58:391–398PubMedCentralPubMedCrossRefGoogle Scholar
  27. Schaeren-Wiemers N, van der Bijl P, Schwab ME (1995) The UDP-galactose:ceramide galactosyltransferase: expression pattern in oligodendrocytes and Schwann cells during myelination and substrate preference for hydroxyceramide. J Neurochem 65:2267–2278PubMedCrossRefGoogle Scholar
  28. Schulte S, Stoffel W (1993) Ceramide UDP-galactosyltransferase from myelinating rat brain: purification, cloning, and expression. Proc Natl Acad Sci U S A 90:10265–10269PubMedCentralPubMedCrossRefGoogle Scholar
  29. Schulte S, Stoffel W (1995) UDP-galactose:ceramide galactosyltransferase and glutamate/aspartate transporter. Copurification, separation and characterization of the two glycoproteins. Eur J Biochem 233:947–953PubMedCrossRefGoogle Scholar
  30. Sprong H, Kruithof B, Leijendekker R, Slot JW, van Meer G, van der Sluijs P (1998) UDP-galactose:ceramide galactosyltransferase is a class I integral membrane protein of the endoplasmic reticulum. J Biol Chem 273:25880–25888PubMedCrossRefGoogle Scholar
  31. Sprong H, Degroote S, Nilsson T, Kawakita M, Ishida N, van der Sluijs P, van Meer G (2003) Association of the Golgi UDP-galactose transporter wit UDP-galactose:ceramide galactosyltransferase allows UDP-galactose import in the endoplasmic reticulum. Mol Biol Cell 14:3482–3493PubMedCentralPubMedCrossRefGoogle Scholar
  32. Stahl N, Jurevics P, Morell K, Suzuki K, Popko B (1994) Isolation, characterization, and expression of cDNA clones that encode rat UDP-galactose:ceramide galactosyltransferase. J Neurosci Res 38:234–242PubMedCrossRefGoogle Scholar
  33. Tencomnao T, Kapitonov D, Bieberich E, Yu RK (2004) Transcriptional regulation of the human UDP-galactose:ceramide galactosyltransferase (hCGT) gene expression: functional role of GC-box and CRE. Glycoconj J 20:339–351PubMedCrossRefGoogle Scholar
  34. van der Bijl P, Strous GJ, Lopes-Cardozo M, Thomas-Oates J, van Meer G (1996) Synthesis of non-hydroxy-galactosylceramides and galactosyldiglycerides by hydroxy-ceramide galactosyltransferase. Biochem J 317:589–597PubMedGoogle Scholar
  35. Yang F, Foekens JA, Yu J, Sieuwerts AM, Timmermans M, Klijn JG, Atkins D, Wang Y, Jiang Y (2006) Laser microdissection and microarray analysis of breast tumors reveal ER-alpha related genes and pathways. Oncogene 25:1413–1419PubMedCrossRefGoogle Scholar
  36. Yonemasu T, Nakahira K, Okumura S, Kagawa T, Espinosa de los Monteros A, de Vellis J, Ikenaka K (1998) Proximal promoter region is sufficient to regulate tissue-specific expression of UDP-galactose:ceramide galactosyltransferase gene. J Neurosci Res 52:757–765PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2014

Authors and Affiliations

  1. 1.Department of BiochemistryKochi University Medical SchoolNankokuJapan

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