UDP-Gal: Ceramide Galactosyltransferase (UGT8)
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.
KeywordsEndoplasmic Reticulum Peripheral Nervous System Seminiferous Tubule Endoplasmic Reticulum Lumen Oligodendrocyte Differentiation
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