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(Received for publication, December 5, 1996, and in revised form, March 19, 1997)
From the Institut für Organische Chemie und Biochemie der
Universität Bonn, Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany
and the ¶ Fakultät für Chemie der Universität
Konstanz, Postfach 5560, 78434 Konstanz, Germany
The effect of six different structurally modified
sphingosine analogues on biosynthesis of sphingolipids was studied in
primary cultured murine cerebellar neurons. Treatment of cells with
cis-4-methylsphingosine at micromolar levels resulted in a
markedly decreased sphingolipid biosynthesis, whereas the other
compounds examined, trans-4-methylsphingosine, cis-5-methylsphingosine,
trans-5-methylsphingosine, cis-sphingosine, and
1-deoxysphingosine, inhibited sphingolipid biosynthesis less efficiently. The inhibition of sphingolipid biosynthesis by the various
compounds was paralleled by a decrease of serine palmitoyltransferase activity in situ. For cis-4-methylsphingosine
the inhibitory effect on serine palmitoyltransferase activity was shown
to be concentration- and time-dependent. Half-maximal
reduction of enzyme activity occurred after 24 h of treatment
with 10 µM of the compound. The activity of other enzymes
of sphingolipid biosynthesis as well as phospholipid and protein
biosynthesis was not affected.
Analysis of the sphingoid moiety of cellular sphingolipids suggests
that the sphingosine analogues listed above were subject to degradation
rather than being utilized as precursors for sphingolipid biosynthesis
by cultured neurons. Except of 1-deoxysphingosine, the other five
sphingosine analogues were shown to be substrates for sphingosine
kinase in vitro. After 24 h of treatment of primary cerebellar neurons with the various sphingosine analogues the relative
percentage of the respective intracellular 1-phosphate derivatives
paralleled exactly the inhibitory effect on serine palmitoyltransferase
activity observed when cells were treated with the unphosphorylated
compounds. In contrast to the respective 1-phosphate derivatives of the
other methyl-branched sphingosine analogues examined,
cis-4-methylsphingosine 1-phosphate showed an intracellular
accumulation suggesting a delayed turnover rate in cultured murine
neurons for this compound. These results suggest that the inhibitory
effect of the sphingosine analogues on serine palmitoyltransferase is
mediated by their respective 1-phosphate derivatives and that the
pronounced effect of cis-4-methylsphingosine is caused by a
high intracellular concentration of
cis-4-methylsphingosine 1-phosphate.
cis-4-Methylsphingosine, in addition,
caused drastic changes in cell morphology of primary cerebellar
neurons, which were not observed when these cells were treated with one
of the other sphingosine analogues examined.
Volume 272, Number 25,
Issue of June 20, 1997
pp. 15825-15833
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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