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New Insights into the Regulation of Serine Palmitoyltransferase

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Technical Report

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Uniformed Services University Of The Health Sciences Bethesda United States

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Sphingolipid biosynthesis starts with condensation of an acyl-CoA chain with Lserineto form 3-ketosphingosine. This committed and rate limiting step is catalyzed by the enzyme serine palmitoyltransferase SPT which is present in all eukaryotes and even in some prokaryotes. The S. cerevisiae SPT is comprised of three ER-associated transmembrane proteins, Lcb Ip, Lcb2p and Tsc3p. The LcbIp and Lcb2p subunits interact directly with each other to form the catalytically active SPT heterodimer. However, the activity of the heterodimer is low, sufficient only to support growth of S.cerevisiae at low e.g., 26 deg. C but not at high e.g., 37 deg. C temperature where more sphingolipid is essential for survival. The activity of the heterodimer is enhanced several fold by the Tsc3p subunit, allowing growth at 37 deg.C. Tsc3p directly binds to the heterodimer and also alters its preference for the acyl-CoA substrate. The Orm proteins are negative regulators of SPT which also directly bind to SPT and down regulate its enzymatic activity. In this study, it has been shown that TMDI of Lcblp is essential for the binding of the Orms to SPT. It was also shown that the Orms have an inhibitory effecton the basal activity of the Lcb 1 p-Lcb2p heterodimer.

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