Studies of the action of ceramide-like substances (d- andl-PDMP) on sphingolipid glycosyltransferases and purified lactosylceramide synthase |
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Authors: | Subroto Chatterjee Tavia Cleveland Wan-Yang Shi Jin-Ichi Inokuchi Norman S Radin |
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Institution: | (1) School of Medicine, Johns Hopkins University, 600 N. Wolfe St, CMSC 604, 21287-3654 Baltimore, MD, USA;(2) Seikagaku Corp., Tokyo Institute, Higashiyamato, 207 Tokyo, Japan;(3) Nephrology Division, University of Michigan Medical School, 48109-0676 Ann Arbor, MI, USA |
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Abstract: | We have studied the effects ofD-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) and itsL-enantiomer on glycosphingolipids in cultured normal human kidney proximal tubular cells. We found thatD-PDMP exerted a concentration-dependent reduction in the metabolic labelling and cellular levels of glucosylceramide (GlcCer), lactosylceramide (LacCer), and the globo-series glycosphingolipids, GbOse3Cer and GbOse4Cer. It also directly inhibited the activity of UDP-glucose:ceramide 1 4-glucosyltransferase (GlcT-1) and UDP-galactose: GlcCer 1 4 galactosyltransferase (GalT-2). In contrast,L-PDMP had opposite effects on the metabolic labelling of GlcCer, LacCer, and GbOse3Cer. The levels of GlcCer and LacCer were increased, while the labelling and level of GbOse4Cer were strongly reduced. Purified GalT-2 from human kidney was inhibited byD-PDMP and stimulated byL-PDMP. It appears likely that the different glycosphingolipid glycosyltransferases possess similar binding sites for the ceramide moiety, which are blocked by binding toD-PDMP and, in the case of GbOse4Cer synthase, byL-PDMP as well. The stimulatory effects ofL-PDMP on GlcCer and LacCer synthases may be the result of binding to a modulatory site on the glycosyltransferases; in intact cells, the enzyme-analog complex may afford protection against the normal catabolic inactivation of the enzymes.Abbreviations GalT-2
UDP-galactose:GlcCer -galactosyltransferase
- GbOse3Cer
Gal 1 4Gal 1 GlcCer
- GbOse4Cer
GalNAc1 3Gal 1 4Gal 1 GlcCer
- GlcCer
glucosylceramide
- GlcT-1
UDP-glucose:ceramide -glucosyltransferase
- GSLs
glycosphingolipids
- LacCer
lactosylceramide
- PDMP
threo-1-phenyl-2-decanolyamino-3-morpholino-1-propanol |
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Keywords: | PDMP (1-phenyl-2-decanoylamino-3-morpholino-1-propanol) glucosylceramide lactosylceramide globotriaosylceramide globotetraosylceramide inhibition and stimulation by PDMP enantiomers |
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