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J Biol Chem, Vol. 274, Issue 8, 4607-4612, February 19, 1999
From the Department of Biological Chemistry, Weizmann Institute of
Science, Rehovot 76100, Israel
In a previous study we observed that long term (5 days) incubation with fumonisin B1 (FB1),
an inhibitor of acylation of sphingoid long chain bases to
(dihydro)ceramide, resulted in morphological and biochemical
changes in 3T3 fibroblasts (Meivar-Levy, I., Sabanay, H., Bershadsky,
A. D., and Futerman, A. H. (1997) J. Biol.
Chem. 272, 1558-1564). Among these were changes in the profile
of synthesis of sphingolipids (SLs) and glycosphingolipids (GSLs).
Whereas [3H]globotriaosylceramide
([3H]Gb3) comprised 1.9% of the total
[3H]SLs and [3H]GSLs synthesized in control
cells, it comprised 16.5% in FB1-treated cells. We now
demonstrate by in vitro analysis that inhibition of
ceramide synthesis by FB1 for 5 days results in
up-regulation of the activities of three enzymes in the pathway of
Gb3 synthesis, namely glucosylceramide, lactosylceramide,
and Gb3 synthases; up-regulation is due to an increase in
Vmax, with no change in Km
values toward lipid substrates. Moreover, molecular analysis (reverse
transcriptase-polymerase chain reaction) of glucosylceramide synthase
indicated that this enzyme is up-regulated at the transcriptional
level. No changes in either the Vmax or Km values of sphingomyelin or of GM3
synthase were detected after FB1 treatment. Analysis of SL
and GSL synthesis in cultured cells using
[4,5-3H]sphinganine as a metabolic precursor demonstrated
that at low substrate concentrations, Gb3 synthesis is
favored over GM3 synthesis and glucosylceramide synthesis
is favored over sphingomyelin synthesis, whereas the opposite is true
at high substrate concentrations. These data demonstrate that GSL
synthesis and in particular Gb3 synthesis are tightly
regulated in fibroblasts, presumably so as to maintain constant levels
of Gb3 on the cell surface.
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