SLI1 (YGR212W) is a major gene conferring resistance to the sphingolipid biosynthesis inhibitor ISP-1, and encodes an ISP-1 N-acetyltransferase in yeast.
ISP-1 (myriocin) is a potent inhibitor of serine palmitoyltransferase, the primary enzyme of sphingolipid biosynthesis, and is a useful tool for studying the biological functions of sphingolipids in both mammals and yeast (Saccharomyces cerevisiae). In a previous study, we cloned yeast multicopy suppressor genes for ISP-1, and one of these, YPK1/SLI2, was shown to encode a serine/threonine kinase which is a yeast homologue of mammalian SGK1 (serum/glucocorticoid-regulated kinase 1). In the present study, another gene, termed SLI1 (YGR212W; GenBank accession number CAA97239.1), was characterized. Sli1p has weak similarity to Atf1p and Atf2p, which are alcohol acetyltransferases. Although a sli1-null strain grew normally, the IC50 of ISP-1 for the growth of this strain was markedly decreased compared with that for the parental strain, indicating that Sli1p is a major contributor to ISP-1 resistance in yeast. On a sli1-null background, the increase in resistance to ISP-1 induced by YPK1 gene transfection was almost abolished. These data indicate that Sli1p co-operates with Ypk1p in mediating resistance to ISP-1 in yeast. Sli1p was found to convert ISP-1 into N-acetyl-ISP-1 in vitro. Furthermore, N-acetyl-ISP-1 did not share the ability of ISP-1 to inhibit the growth of yeast cells, and the serine palmitoyltransferase inhibitory activity of N-acetyl-ISP-1 was much lower than that of ISP-1. These data suggest that Sli1p inactivates ISP-1 due to its N-acetyltransferase activity towards ISP-1.
Momoi
Michiko
M
Laboratory of Membrane Biochemistry and Biophysics, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.
Tanoue
Daisuke
D
Sun
Yidi
Y
Takematsu
Hiromu
H
Suzuki
Yusuke
Y
Suzuki
Minoru
M
Suzuki
Akemi
A
Fujita
Tetsuro
T
Kozutsumi
Yasunori
Y
D000107:Acetylation; D000123:Acetyltransferases / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D000935:Antifungal Agents; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D025141:Drug Resistance, Fungal / Q000235:genetics / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism* / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D016366:Open Reading Frames / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D013107:Sphingolipids / Q000378:metabolism*
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D013107:Sphingolipids; D049452:Green Fluorescent Proteins; D000123:Acetyltransferases; C492826:SLI1 protein, S cerevisiae; D001191:Arylamine N-Acetyltransferase; C001996:thermozymocidin