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J. Biol. Chem., Vol. 276, Issue 38, 35614-35621, September 21, 2001
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From the Departments of ¶ Medicine and
In the yeast Saccharomyces
cerevisiae, we have demonstrated a necessary role for
sphingolipids in the heat stress response through inhibition of
nutrient import (Chung, N., Jenkins, G. M., Hannun, Y. A., Heitman, J., and Obeid, L. M. (2000) J. Biol. Chem. 275, 17229-17232). In this study, we used a combination of
pharmacological and genetic approaches to determine which endogenous sphingolipid is the likely mediator of growth inhibition. When cells
were treated with exogenous phytosphingosine (PHS, 20 µM) or structurally similar or metabolically related molecules, including 3-ketodihydrosphingosine, dihydrosphingosine,
C2-phytoceramide (PHC), and stearylamine, only PHS
inhibited growth. Also, PHS was shown to inhibit uptake of uracil,
tryptophan, leucine, and histidine. Again this effect was specific to
PHS. Because of the dynamic nature of sphingolipid metabolism, however,
it was difficult to conclude that growth inhibition was caused by PHS
itself. By using mutant yeast strains defective in various steps in
sphingolipid metabolism, we further determined the specificity of PHS.
The elo2
Phytosphingosine as a Specific Inhibitor of Growth and Nutrient
Import in Saccharomyces cerevisiae*
§,
**,, and Biochemistry and Molecular Biology, Medical
University of South Carolina, Charleston, South Carolina 29425 and
the Departments of Pharmacology & Cancer Biology,
Genetics, Microbiology, and Medicine, and the Howard Hughes
Medical Institute, Duke University Medical Center,
Durham, North Carolina 27710
strain, which is defective in the conversion of
PHS to PHC, was shown to have slower biosynthesis of ceramides and to
be hypersensitive to PHS (5 µM), suggesting that PHS does
not need to be converted to PHC. The lcb4 lcb5 strain
is defective in the conversion of PHS to PHS 1-phosphate, and it was as
sensitive to PHS as the wild-type strain. The syr2
mutant strain was defective in the conversion of DHS to PHS.
Interestingly, this strain was resistant to high concentrations of DHS
(40 µM) that inhibited the growth of an isogenic
wild-type strain, demonstrating that DHS needs to be converted to PHS
to inhibit growth. Together, these data demonstrate that the active
sphingolipid species that inhibits yeast growth is PHS or a closely
related and yet unidentified metabolite.
*
This work was supported in part by National
Institutes of Health Grants AG16583 (to L. M. O.), GM43825 (to
Y. A. H.), HL43707 (to Y. A. H.), and AI41937 (to J. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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